CN110938109A

CN110938109A - O-quinone compound, preparation method and medical application thereof

Info

Publication number: CN110938109A
Application number: CN201911147367.5A
Authority: CN
Inventors: 郝海平; 蒋晟; 卢之瑀; 王德祥; 张阔军; 张文波; 钱振龙; 韩佳玲; 张婉衡; 郑啸
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2019-11-21
Filing date: 2019-11-21
Publication date: 2020-03-31
Anticipated expiration: 2039-11-21
Also published as: CN110938109B

Abstract

The invention discloses an active small molecule compound simultaneously targeting NQO1 and NAMPT, a preparation method and medical application thereof, and in particular relates to an o-quinone compound or pharmaceutically acceptable salts, solvates, prodrugs, esters, racemates and isomers thereof, a pharmaceutical composition containing the compound, and application of the compound or the pharmaceutical composition in preparing antitumor drugs. The invention reasonably splices the pharmacophores of NQO1 which can activate the tanshinone IIA and the NAMPT inhibitor to obtain the NQO1 substrate/NAMPT inhibitor, and the compounds can be reduced and activated by NQO1 and can inhibit the activity of NAMPT, thereby consuming NAD + and inhibiting NAD +⁺Shows stronger swellingTumor inhibitory activity. The o-quinone derivative or the pharmaceutical composition thereof simultaneously targeting NQO1 and NAMPT has wide application prospect and is expected to become an anti-tumor drug.

Description

O-quinone compound, preparation method and medical application thereof

Technical Field

The invention belongs to the field of chemical medicine, and particularly relates to an o-quinone compound, pharmaceutically acceptable salts and prodrug molecules thereof, a pharmaceutical composition containing the compound and application of the compound or the composition in preparation of medicines.

Background

Nicotinamide adenine dinucleotide (NAD for short)⁺) Is an important cofactor of many redox reactions in energy metabolism processes including oxidative phosphorylation, glycolysis, pentose phosphate pathway, etc., and is also a substrate of many key enzymes in signal transduction processes, such as deacetylation and ADP ribosylation of acetylase (SIRT), poly-ADP-ribosylation of poly-ADP-ribose polymerase (PARP), etc. In addition, NAD⁺And the reduced NADH thereof have important significance for maintaining the reducing environment in the cells so as to protect the cells from being damaged by oxidative stress. Thus, intracellular NAD⁺Is a critical factor in determining cell fate. Tumor cells have an uncontrollable proliferation rate, a rapid metabolic rate, and a significantly increased level of oxidative stress relative to normal cells, and thus tumor cells are sensitive to NAD⁺The level change is more sensitive. NAD (nicotinamide adenine dinucleotide)⁺Key enzymes of the in vivo biosynthetic pathway have become important targets for anticancer drugs. NAD (nicotinamide adenine dinucleotide)⁺There are several synthetic pathways in vivo: one is a de novo synthesis route using tryptophan as a starting material and the other three are nicotinamide (NAM for short)) A remediative synthesis way taking nicotinic acid (NA for short) and nicotinamide ribose (NR for short) as starting materials. The salvage synthesis route using NAM as the starting material is the in vivo supply of NAD⁺The most important pathway, nicotinamide phosphoribosyltransferase (NAMPT) is the key rate-limiting enzyme catalyzing this process (Galli U.et al.J.Med.chem.2013,22,56(16): 6279-96). Tumor cells proliferate at a much higher rate and energy demand than normal cells, and therefore are more dependent on NAD + and more sensitive to changes in NMAPT activity. A large number of NAMPT inhibitors have been reported, the most typical of which are FK866 and CHS828 entering clinical studies, but have the problems of short half-life, dose-dependent toxicity and the like (Montecco F. et. curr. drug targets.2013,1,14(6): 637-43). Therefore, FK866 and CHS828 lack selectivity for tumor cells and are not suitable for single dose administration.

Reduced coenzyme I quinone oxidoreductase (NAD (P) H quinone oxidase reductase-1: NQO1) is a ubiquitous FAD-dependent flavoprotein enzyme, and participates in the metabolism of various quinone compounds and the biological activation process of quinone drugs in vivo by catalyzing two-electron reduction reaction. Generally, the NQO 1-mediated reduction protects the body from malignant attack by electrophilic quinones, bypasses one-electron reduction so that the quinones bypass reactive semiquinones to directly produce hydroquinone, which is further subjected to conjugation reaction with glutathione, glucuronic acid, sulfate, etc. in vivo and is excreted out of the body. NQO1 is an important cytoprotective mechanism in vivo. However, a great deal of literature reports that NQO1 is highly expressed in various tumor cells and is closely related to the occurrence and development of tumors, metastasis, drug resistance and the like. In addition, the NQO 1-mediated reduction reactions are not all detoxification processes and the hydroquinones produced are not all stable. The antitumor quinones compound can generate corresponding hydroquinone under the reduction action of NQO1, and generate a large amount of active oxygen (reactive oxygen species) through DNA alkylationpecies, ROS) induces DNA damage and the like to selectively kill tumor cells. Tanshinone IIA is an important NQO1 activated substrate, corresponding hydroquinone is generated under the catalytic action of NQO1, the hydroquinone consumes two molecular of oxygen and returns to the quinone, and 2mol of superoxide anion (O) is generated at the same time₂ ^·–) Superoxide anion (O)₂ ^·–) Further generating Hydrogen peroxide (H) under the action of Superoxide dismutase (SOD)₂O₂). H due to high NQO1 expression and low Catalase (Catalase, CAT) expression in tumor cells₂O₂The life cycle is longer and the DNA spreads into the cell nucleus quickly, which causes the breakage of DNA base and single strand, thereby causing the high expression of poly (ADP-ribose) polymerase 1, PARP-1, and then NAD⁺Is largely consumed, selectively kills tumor cells with high expression of NQO1 (Liu et al plos one.2012,7, e 42138).

The literature reports that NQO1 can activate substrate tanshinone IIA to consume NAD + and simultaneously can feedback-raise the expression of NAMPT, and the combined administration of tanshinone IIA and NAMPT inhibitor FK866 can greatly consume NAD + and simultaneously inhibit the generation of NAD +, thereby exerting the synergistic antitumor effect, simultaneously reducing the dosage of the two drugs, reducing the toxic and side effects, increasing the curative effect, widening the therapeutic window, improving the therapeutic index (Liu et al.Chin.J.nat.Med.2016,14,582 589), but the combined administration has the problems of easy generation of drug-drug interaction, complex pharmacokinetic properties, incapability of ensuring that two (multiple) drugs reach the therapeutic target, poor compliance of patients and the like.

Disclosure of Invention

The purpose of the invention is as follows: aiming at the defects in the prior art, the invention provides an active small molecular compound simultaneously targeting NQO1 and NAMPT, which is used for solving the problems of weak curative effect, large toxic and side effect and the like of the existing anticancer drugs. The invention also provides a preparation method and pharmaceutical application of the compound.

The technical scheme is as follows: the invention relates to an o-quinone compound shown in a general formula I, or pharmaceutically acceptable salt, solvate, prodrug, ester, raceme and isomer thereof:

in formula I:

r is unsubstituted or R¹Substituted C_6-10Aryl, unsubstituted or R²Substituted 'hetero atom selected from one or more of N, O and S, 5-10 membered heteroaryl with 1-3 hetero atoms', unsubstituted or R³A substituted 5-to 10-membered heterocycloalkyl group containing one or more heteroatoms selected from N, O and S and having 1 to 3 heteroatoms; wherein R is¹、R²And R³Independently is deuterium, halogen, hydroxy, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6A haloalkyl group.

Y is a single bond, C_2-4Olefinic bond, C_1-4Alkyl, cyclopropyl, -NHCH₂-；

E is O, S or N-C ≡ N;

l is-NR⁴-(CH₂)n-、

Wherein R is⁴And R⁵Independently selected from hydrogen, C₁-₆Alkyl, hydroxy- (C)_1-6Alkyl) -, C_6-10Aryl radical, C₃-C₆Cycloalkyl radical, C_6-10Aryl radical- (C)_1-6Alkyl) -, C₃-C₆Cycloalkyl radicals-(C_1-6Alkyl) -, or,

n＝0-8。

In the present invention, when R is unsubstituted or R²When the substituted 'hetero atom is selected from one or more of N, O and S, and 5-10 membered heteroaryl with 1-3 hetero atoms', R is²Is one or more, when there are more than one R²When R is said²The same or different;

when R is unsubstituted or R²When the substituted 'hetero atom is selected from one or more of N, O and S, and 5-10 membered heteroaryl with 1-3 hetero atoms', the heteroaryl is '5-10 membered heteroaryl with 1-3 hetero atoms and at least 1N atom', wherein the hetero atoms are selected from one or more of N, O and S;

when R is unsubstituted or R³When the substituted' hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-3, and the heterocyclic alkyl is 5-10-membered³Is one or more, when there are more than one R³When R is said³The same or different;

when R is unsubstituted or R³When the substituted ' heteroatom is selected from one or more of N, O and S, and the heteroatom number is 5-10-membered ' heterocycloalkyl with 1-3 atoms ', the heterocycloalkyl is ' 5-10-membered ' heterocycloalkyl with the heteroatom selected from one or more of N, O and S, the heteroatom number is 1-3, and the N atom number is at least 1;

when R is²Is C_1-6When there is an alkyl group, said C_1-6Alkyl of (A) is C_1-3Alkyl, preferably methyl;

when R is²Is C_1-6Alkoxy of (2), said C_1-6Alkoxy of C_1-3Alkoxy of (b), preferably methoxy;

when R is²Is C_1-6When halogenated alkyl, said C_1-6Haloalkyl being C_1-3Haloalkyl, preferably trifluoromethyl;

when R is³Is C_1-6When there is an alkyl group, said C_1-6Alkyl of (A) is C_1-3Alkyl, preferably methyl;

when R is³Is C_1-6Alkoxy of (2), said C_1-6Alkoxy of C_1-3Alkoxy, preferably methoxy;

when R is³Is C_1-6When halogenated alkyl, said C_1-6Haloalkyl being C_1-3Haloalkyl, preferably trifluoromethyl.

In the present invention, when E is O, Y is a single bond, C_1-4Alkyl radical, C_2-4Alkenyl, cyclopropyl, -NH-CH₂-, or, when E is S, Y is-NH-CH₂-or, alternatively, when E is N-C ≡ N, Y is a single bond;

when L is-NR⁴-(CH₂) n-where n is 2-6, preferably n is 4,5 or 6; when L is

When n is 0-2; when L is

When n is 0-2; when L is

When n is 0-2; when L is

When n is 0-2; when L is

When n is 0-2;

in the present invention, when R is⁴Is C_1-6When alkyl, said C_1-6Alkyl is C_1-4Alkyl, preferably methyl, ethyl, propyl and isopropyl; when R is⁴Is hydroxy- (C)_1-6Alkyl) -hydroxy- (C)_1-6Alkyl) -is hydroxy- (C)_1-4Alkyl) -, preferably hydroxyethyl; when R is⁴Is C_6-10When aryl, said C_6-10Aryl is phenyl; when R is⁴Is C_6-10Aryl radical- (C)_1-6Alkyl) -said C_6-10Aryl radical- (C)_1-6Alkyl) -is phenyl- (C)_1-4Alkyl) -, preferably benzyl, phenethyl; when R is⁴Is C₃-C₆Cycloalkyl- (C)_1-6Alkyl) -said C₃-C₆Cycloalkyl- (C)_1-6Alkyl) -is

In the present invention, when R is unsubstituted or R²When the substituted 'hetero atom is selected from one or more of N, O and S, and 5-10 membered heteroaryl with 1-3 hetero atoms', R is³The number of (a) is 1,2 or 3;

when R is unsubstituted or R²When the substituted ' 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S ' is substituted ', the heteroaryl is:

when R is unsubstituted or R³When the substituted 5-to 10-membered heterocycloalkyl with 1 to 3 heteroatoms selected from N, O and S is one or more than one, the heterocycloalkyl is

When R is⁴Is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, isopropyl;

when R is⁴Is C_6-10Aryl radical- (C)_1-6Alkyl) -said C_6-10Aryl radical- (C)_1-6Alkyl) -is benzyl, phenethyl, phenylpropyl, preferably benzyl;

when R is unsubstituted or R²Substituted "hetero atoms selected from one or more of N, O and S, hetero atoms(iii) when the number of the subgroups is 1-3, the heteroaryl group is 5-10 membered²Substituted heteroaryl groups are:

when R is unsubstituted or R³When substituted' 5-10 membered heterocycloalkyl with 1-3 hetero atoms selected from one or more of N, O and S is unsubstituted or R³Substituted heterocycloalkyl is:

in the invention, when E is O, Y is a single bond, R is:

or, when E is O, Y is-NH-CH₂-、C_2-4Alkenyl or cyclopropyl, R is:

or, when E is S, Y is-NH-CH₂-, R is:

or, when E is N-C ≡ N, Y is C_1-4Alkyl, R is:

or, when E is O and Y is cyclopropyl, R is:

in the invention, the compound shown in the formula I is any one of the following compounds:

the invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps: in a solvent, carrying out chloromethylation reaction on a compound 1 under the action of HCl gas to generate a compound 2, and then carrying out substitution reaction on the compound shown as a formula II and the compound 2 under the action of alkali;

wherein L, Y, E and R are as defined in claim 1.

The compound 1 is subjected to chloromethylation reaction under the action of HCl gas, the reaction time is preferably 1.5-3 h, the reaction temperature is preferably 45-65 ℃, and the reaction solvent is preferably 1, 4-dioxane, ethyl acetate, tetrahydrofuran and the like.

The compound 2 and the intermediate compound II are subjected to substitution reaction to generate a compound I, the reaction temperature is 45-65 ℃, and the reaction solvent is preferably acetone, acetonitrile, tetrahydrofuran, N-dimethylformamide and the like.

Wherein, the compound II is prepared by adopting a conventional preparation method.

In the present invention, after the substitution reaction is completed, it may preferably further include a post-treatment step. The post-treatment conditions and operations may be those conventional in the art, including the steps of: cooling the reaction solution, adding a solvent, extracting to obtain an organic layer, drying, filtering, removing the solvent in the filtrate to obtain a residue, and separating and purifying the residue. The cooling is preferably to room temperature. The solvent is preferably a salt solution, such as a saturated salt solution. The extraction conditions and operations may be those conventional in the art, and the solvent for the extraction is preferably an ester solvent, such as ethyl acetate. The drying conditions and procedures may be those conventional in the art, and the dried reagent may be one conventional in the art, such as anhydrous sodium sulfate. The conditions and operations of the filtration can be those conventional in the art. The conditions and operations for removing the solvent can be those conventional in the art, such as evaporating the solvent. The separation and purification is preferably column chromatography separation.

The term "room temperature" as used herein means 20 to 30 ℃ unless otherwise specified.

The invention also provides a pharmaceutical composition, which comprises the compound shown as the general formula I, or pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof, and pharmaceutic adjuvants.

In the pharmaceutical composition, the compound shown in formula I, a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, a metabolite thereof, a metabolic precursor thereof, or a prodrug thereof can be used in a therapeutically effective amount.

The invention also provides a compound shown as the general formula I, or pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof or a pharmaceutical composition thereof in the preparation of reduced coenzyme I: quinone oxidoreductase substrates and nicotinamide phosphoribosyltransferase inhibitors.

The invention also provides application of the compound shown as the formula I, or pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof in preparing medicaments.

The invention also provides a compound shown as the formula I, or pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof, and the medicine can be used for tumors.

The invention also provides application of the pharmaceutical composition in preparing a medicament for treating tumors.

In the present invention, the tumor includes, but is not limited to, non-small cell lung cancer, breast cancer, pancreatic cancer or prostate cancer.

The pharmaceutical excipients can be those widely used in the field of pharmaceutical production. The excipients are used primarily to provide a safe, stable and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate or for promoting the effective absorption of the active ingredient after administration of the composition by a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

In the compounds of the present invention, when any variable occurs more than one time in any constituent, its definition in each occurrence is independent of its definition in every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the invention may be selected by one of ordinary skill in the art to provide compounds of interest that are chemically stable and that can be readily synthesized from readily available starting materials by those of ordinary skill in the art and by methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.

The term "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, such as the medically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art.

The term "isomer" refers to two or more compounds that are identical in molecular composition but differ in structure and properties.

The term "racemate" refers to an equimolar mixture of a chiral molecule and its enantiomer having optical activity, which is formed by mixing equal amounts of molecules having opposite optical rotation directions and the same optical activity, and whose optical activity is offset by the interaction between these molecules, and thus is optically inactive.

The term "solvate" refers to a mixture of a compound and a solvent, e.g., a crystalline form is a solvate.

The term "prodrug" refers to a compound that is rapidly converted in vivo by hydrolysis in blood to yield the parent compound having the above formula.

The compounds of the present invention may form salts. The "salt" in the present application means an acid salt with an inorganic acid or an organic acid, and a basic salt with an inorganic base or an organic base. In addition, when the compounds have a basic moiety (e.g., pyridine, imidazole, etc.) and an acidic moiety (e.g., carboxylic acid), zwitterions ("inner salts") may form and are also included within the term "salt(s)" as used herein. Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of the compounds are formed by reaction with a suitable inorganic or organic base. Pharmaceutically acceptable, non-toxic, physiologically acceptable salts are preferred, although other salts are also useful.

Exemplary non-toxic acid salts include salts prepared from inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, acetic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, glycerophosphoric acid, salicylic acid, sulfanilic acid, fumaric acid, 2-acetoxy-benzoic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, and trifluoroacetic acid, and the like.

Exemplary non-toxic basic salts include salts from inorganic bases such as aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc and the like, as well as salts from organic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, glycine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, methylglucamine, histidine, lysine, isopropylamine, morpholine, piperidine, polyamine resins, procaine, purines, theobromine, and the like, Triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

The term "free form" as opposed to "salt" form means that the compound of formula I is present in a non-salt form. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.

When the linking group as exemplified does not indicate its direction of attachment, its direction of attachment is in the same direction as the reading from left to right, for example

The linking group L in (A) is

At this time, the

And

is connected, - (CH)₂)_n-and

and (4) connecting.

As will be understood by those skilled in the art, the present invention is based on conventions used in the artAs used in the structural formulae of the radicals

Means that the corresponding group is connected with other fragments and groups in the compound shown in the formula I through the site.

The "substitution" in the present invention may be one or more, and when there are a plurality of "substitutions", the "substitutions" may be the same or different.

The term "plurality" means 2,3, 4 or 5. For example, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having the specified number of carbon atoms. Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, tert-butyl, neopentyl, n-hexyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 4-methyl-2-pentyl. It should be noted that, when the number of carbon atoms thereof is not particularly limited, it refers only to the number of carbon atoms of the alkyl moiety specified therein, and does not include the number of carbon atoms on the substituent of the alkyl group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkoxy" refers to the group-O-R^YWherein R is^YIs an alkyl group as defined above.

The term "cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group. The monocyclic cycloalkyl group is preferably a monovalent saturated cyclic alkyl group having 3 to 7 ring carbon atoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Each ring of the polycyclic cycloalkyl is saturated and can be a bicyclic or tricyclic cycloalkyl having 4 to 10 carbon atoms.

The term "heterocycloalkyl" as used herein means a bicyclic ring formed by fusing a saturated monocyclic ring having a heteroatom or a saturated monocyclic ring containing a heteroatom with a heteroaryl, and when the term "heterocycloalkyl" is a bicyclic ring formed by fusing a saturated monocyclic ring containing a heteroatom with a heteroaryl, the "heterocycloalkyl" is linked to other fragments or groups in the compound of formula I through a saturated monocyclic ring containing a heteroatom.

The term "aryl" refers to an aromatic group having the indicated number of carbon atoms, preferably a monocyclic, bicyclic or tricyclic aromatic group, each of which, when bicyclic or tricyclic, satisfies the huckel rule. C of the invention_6-10The aryl group of (b) means an aromatic group having 6 to 10 carbon atoms, such as phenyl or naphthyl.

The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably an aromatic 5-6 membered monocyclic or 9-10 membered bicyclic ring containing 1,2 or 3 members independently selected from nitrogen, oxygen and sulfur. The 5-to 6-membered monocyclic ring includes, but is not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, furazanyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazolyl, dithiazolyl, tetrazolyl, pyridyl, pyranyl, thiopyranyl, diazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, or tetrazinyl. The 9-to 10-membered bicyclic ring comprises, but is not limited to, benzimidazolyl, benzisothiazolyl, benzoxazolyl, imidazopyridine, thiazolopyridine, furopyridine and tetrahydropyrrolopyridine.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) phenyl) acrylamide

The method comprises the following steps: (E) synthesis of (6a) -N- (4-aminophenyl) -3- (pyridin-3-yl) acrylamide hydrochloride

(E) -3- (3-pyridine) acrylic acid 3(500mg, 3.35mmol) was weighed out and dissolved in anhydrous DMF (10mL), HATU (1.9g, 5.03mmol), DIPEA (10.05mmol, 1.3g) and N-BOC-p-phenylenediamine 4a (697.7mg, 3.35mmol) were added in this order, the reaction was stirred at room temperature for 2h, stopped, and DMF was spin-dried under reduced pressure. 5ml of saturated NaHCO was added to the reaction residue₃Solution, DCM (20 ml. times.3), combined organic phases, saturated NH₄Cl (10ml) was washed 1 time, saturated brine (10ml) was washed 1 time, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, and subjected to sand making and column chromatography separation and purification (DCM: MeOH 60: 1-20: 1) to obtain 5a 968mg (85%) of a brown solid.¹H NMR(300MHz,DMSO-d₆)δ:10.21(s,1H),9.29(s,1H),8.81(s,1H),8.58(dd,J＝4.8,1.6Hz,1H),8.02(d,J＝7.5Hz,1H),7.66–7.55(m,3H),7.51–7.38(m,3H),6.93(d,J＝15.8Hz,1H),1.47(s,9H).¹³C NMR(75MHz,DMSO-d₆)δ:162.7,152.9,150.3,149.2,136.4,135.3,134.1,133.7,130.7,124.4,124.1,119.8,118.6,78.9,28.2.

340mg of the white solid is weighed, 2mL of ethyl acetate is added, 2mL of HCl/ethyl acetate solution (3M) is added into the suspension, the mixture is stirred for 3 hours at room temperature, after the reaction is completed, the mixture is directly filtered, the filter cake is washed by ethyl acetate, and the hydrochloride 6a is obtained by vacuum drying and is directly reacted in the next step without purification.

Step two: synthesis of 2- (chloromethyl) -1,6, 6-trimethyl-6, 7,8, 9-hexahydro-phenanthrene [1,2-b ] furan-10, 11-dione (2)

Weighing raw material 1(5g, 0.22mol) and dissolving in 1, 4-dioxane (120mL), adding paraformaldehyde (6.6g, 2.2mol), introducing hydrogen chloride gas into the reaction solution, heating to 45 ℃, and stirring for reaction for 1.5 h. And stopping the reaction, pouring the reaction solution into 200mL of ice water, carrying out suction filtration, washing the filter cake with water, and carrying out vacuum drying to obtain a dark red solid 2 which is directly put into the next reaction without purification.

Step three: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) phenyl) acrylamide (S1)

To hydrochloride salt 6a (94mg, 0.30mmol) was added DMF (5mL), K₂CO₃(124mg,0.90mmol), TEA (0.083mL, 0.60mmol) and Compound 2(100mg, 0.30mmol) were heated to 60 ℃ and stirred for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, DMF was spin-dried under reduced pressure, and DCM (10mL) was added to dissolve the DMF, the DMF was washed with water 1 time (5mL), saturated brine was washed with water 1 time (5mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, prepared into sand, and separated and purified by column chromatography (DCM: MeOH 60: 1-40: 1) to obtain S1(85mg, 52%) as a red solid.¹H NMR(300MHz,DMSO-d6)δ:9.94(s,1H),8.79(d,J＝1.6Hz,1H),8.64–8.51(m,1H),8.01(d,J＝7.8Hz,1H),7.80(d,J＝8.2Hz,1H),7.60–7.42(m,5H),6.88(d,J＝16.0Hz,1H),6.68(d,J＝8.8Hz,1H),6.08(t,J＝6.0Hz,1H),4.31(d,J＝8.0Hz,2H),3.06(t,J＝5.7Hz,2H),2.23(s,3H),1.78–1.67(m,2H),1.66–1.57(m,2H),1.27(s,6H).¹³C NMR(126MHz,DMSO)δ:182.5,175.0,162.2,159.0,151.7,150.1,149.2,149.1,144.6,142.8,135.6,133.9,133.4,130.70,129.0,126.6,126.4,124.6,124.0,120.8,120.0,119.8,116.1,112.4,54.9,38.0,37.4,34.3,31.4,29.4,18.7,8.5.ESI-HRMS m/z calculatedfor C₃₄H₃₂N₃O₄[M+H]⁺546.23873,found 546.23859.

The compounds S2-S4 in the following examples 2-4 can be obtained by the synthesis method of example 1, and only the corresponding raw materials need to be replaced.

Example 2: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (4- (1- ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthro [1,2-b ] furan-2-yl) methyl) piperidin-4-yl) phenyl) acrylamide (S2)

¹H NMR(300MHz,DMSO-d₆)δ10.22(s,1H),8.81(s,1H),8.58(d,J＝4.7Hz,1H),8.03(d,J＝8.0Hz,1H),7.79(d,J＝8.2Hz,1H),7.75–7.53(m,4H),7.48(dd,J＝8.0,4.8Hz,1H),7.20(d,J＝8.2Hz,2H),6.91(d,J＝15.8Hz,1H),3.60(s,2H),3.10–3.02(m,2H),2.98(d,J＝10.5Hz,2H),2.41(d,J＝11.9Hz,1H),2.19(s,3H),2.14(d,J＝10.9Hz,2H),1.84–1.67(m,4H),1.67–1.55(m,4H),1.28(s,6H).¹³C NMR(126MHz,Chloroform-d)δ:183.8,176.0,163.4,161.0,150.6,150.3,149.3,144.6,142.5,138.5,136.3,134.7,133.9,130.8,127.5,127.5,126.6,123.9,123.4,120.7,120.5,120.4,119.3,54.0,52.6,41.9,38.0,34.8,33.4,32.0,30.1,19.3,9.2.ESI-HRMS m/z calculated for C₃₉H₄₀N₃O₄[M+H]⁺614.30133,found 614.30093.

Example 3: (E) -3- (pyridin-3-yl) -N- (4- ((2- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthro [1,2-b ] furan-2-yl) methyl) amino) ethyl) amino) phenyl) acrylamide (S3)

¹H NMR(300MHz,DMSO-d₆)δ:8.75(d,J＝2.1Hz,1H),8.62–8.45(m,1H),8.22(t,J＝5.7Hz,1H),8.00(d,J＝8.0Hz,1H),7.76(d,J＝8.2Hz,1H),7.52–7.39(m,3H),6.99(d,J＝8.0Hz,2H),6.73(d,J＝15.9Hz,1H),6.64(d,J＝8.1Hz,2H),4.27(s,2H),3.38–3.25(m,2H),3.02(d,J＝6.5Hz,2H),2.62(t,J＝7.5Hz,2H),2.20(s,3H),1.75–1.64(m,2H),1.63–1.53(m,2H),1.26(s,6H).¹³C NMR(126MHz,DMSO-d₆)δ:182.4,175.0,164.3,159.0,151.7,149.5,149.2,148.6,148.5,146.4,142.8,134.9,134.5,134.4,133.4,131.0,129.1,127.2,126.6,126.4,124.6,124.5,124.2,124.2,120.0,119.8,116.2,112.6,40.7,38.0,37.4,34.3,34.2,31.5,29.5,18.7,8.5.ESI-HRMS m/z calculated for C₃₆H₃₆N₃O₄[M+H]⁺574.27003,found 574.26959.

Example 4: synthesis of N- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) phenyl) imidazo [1,2-a ] pyridine-6-carboxamide (S4).

¹H NMR(300MHz,DMSO-d6)δ:10.04(s,1H),9.20–9.18(m,1H),8.09(s,1H),7.80(d,J＝8.2Hz,1H),7.76-7.70(m,1H),7.70–7.61(m,2H),7.53(d,J＝8.2Hz,1H),7.47(d,J＝8.9Hz,1H),6.71(d,J＝8.9Hz,2H),6.10(s,1H),4.33(d,J＝4.2Hz,2H),3.06(t,J＝6.2Hz,2H),2.24(s,3H),1.78–1.66(m,2H),1.64–1.56(m,2H),1.27(s,6H).¹³C NMR(126MHz,DMSO-d6)δ:182.5,175.0,162.5,159.0,151.7,149.2,144.9,144.5,142.8,134.4,133.4,128.5,128.4,126.6,126.4,123.1,122.1,120.4,120.0,119.7,116.1,116.0,114.2,112.3,38.0,37.4,34.3,31.4,29.4,18.7,8.5.ESI-HRMS m/z calculatedfor C₃₄H₃₁N₄O₄[M+Na]⁺581.21593,found 581.21597.

Example 5: (E) synthesis of (E) -1,6, 6-trimethyl-2- ((4- (3- (pyridin-3-yl) acryloyl) piperazin-1-yl) methyl) -6,7,8, 9-hexahydrophenanthrene [1,2-b ] furan-10, 11-dione (S5)

The method comprises the following steps: (E) synthesis of (E) -1- (piperazin-1-yl) -3- (pyridin-3-yl) prop-2-en-1-one (8a)

(E) -3- (3-pyridine) acrylic acid 3(500mg, 3.35mmol) was weighed, dissolved in anhydrous DMF (10mL), EDCI (1.1g, 5.7mmol), HOBt (595mg, 4.4mmol), TEA (0.92mL,6.7mmol) and compound 8a (623.9mg, 3.35mmol) were added successively, the reaction was stirred at room temperature for 5h, stopped, and DMF was spin-dried under reduced pressure. 5ml of saturated NaHCO was added to the reaction residue₃Solution, DCM (20 ml. times.3), combined organic phases, saturated NH₄Washed with Cl (10ml) for 1 time, washed with saturated brine (10ml) for 1 time, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, granulated, and purified by column chromatography (DCM: MeOH: 60: 1-20: 1) to give 9a 871mg (82%) of a white solid.¹H NMR(300MHz,Chloroform-d)δ:8.76(d,J＝2.1Hz,1H),8.58(d,J＝4.8Hz,1H),7.93–7.77(m,1H),7.67(d,J＝15.5Hz,1H),7.32(dd,J＝8.0,4.8Hz,1H),6.93(d,J＝15.5Hz,1H),3.67(d,J＝20.9Hz,4H),3.49(s,4H),1.48(s,9H).¹³CNMR(75MHz,Chloroform-d)δ:165.0,154.7,150.6,149.3,139.7,134.5,131.0,123.8,119.1,80.57,28.51.

317mg of the white solid is weighed, 2mL of ethyl acetate is added, 2mL of HCl/ethyl acetate solution (3M) is added into the suspension, the mixture is stirred for 3 hours at room temperature, after the reaction is completed, the mixture is directly filtered, the filter cake is washed by ethyl acetate, and the hydrochloride 9a is obtained by vacuum drying and is directly reacted in the next step without purification.

Step three: (E) synthesis of (E) -1,6, 6-trimethyl-2- ((4- (3- (pyridin-3-yl) acryloyl) piperazin-1-yl) methyl) -6,7,8, 9-hexahydrophenanthrene [1,2-b ] furan-10, 11-dione (S5)

To hydrochloride salt 9a (87mg, 0.30mmol) was added DMF (5mL), K₂CO₃(124mg,0.90mmol), TEA (0.083mL, 0.60mmol) and Compound 2(100mg, 0.30mmol) were heated to 60 ℃ and stirred for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature, DMF was spin-dried under reduced pressure, and DCM (10mL) was added to dissolve the DMF, the DMF was washed with water 1 time (5mL), saturated brine was washed with water 1 time (5mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, prepared into sand, and separated and purified by column chromatography (DCM: MeOH 60: 1-40: 1) to obtain S1(94mg, 70%) as a red solid.

¹H NMR(300MHz,Chloroform-d)δ:8.73(s,1H),8.56(d,J＝4.0Hz,1H),7.79(d,J＝7.8Hz,1H),7.69–7.54(m,3H),7.34–7.27(m,1H),6.92(d,J＝15.5Hz,1H),3.73(d,J＝23.1Hz,4H),3.63(s,2H),3.17(t,J＝5.8Hz,2H),2.58(s,4H),2.25(s,3H),1.82–1.74(m,2H),1.71–1.56(m,2H).¹³C NMR(126MHz,Chloroform-d)δ:183.7,175.9,164.8,160.9,150.5,150.4,149.4,149.3,144.7,139.5,134.4,133.5,131.1,127.3,126.7,123.8,120.6,120.4,119.6,119.2,53.0,52.5,52.2,45.9,42.3,38.0,34.8,32.0,30.0,19.2,9.1.ESI-HRMS m/z calculated for C₃₂H₃₄N₃O₄[M+H]⁺524.25438,found 524.25404.

The compounds S6 to S31 in the following examples 6 to 31 can be obtained by the synthesis method of example 5, and only the corresponding raw materials need to be replaced.

Example 6: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (1- ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) piperidin-4-yl) acrylamide (S6)

¹H NMR(300MHz,Chloroform-d)δ:¹H NMR(300MHz,Chloroform-d)δ8.74(s,1H),8.55(d,J＝4.0Hz,1H),7.79(d,J＝7.7Hz,1H),7.68–7.54(m,3H),7.29(t,J＝5.8Hz,1H),6.56(d,J＝15.6Hz,1H),6.10(d,J＝4.7Hz,1H),3.97(d,J＝7.5Hz,1H),3.62(s,2H),3.17(t,J＝6.0Hz,2H),2.95(d,J＝8.4Hz,2H),2.33(d,J＝11.0Hz,2H),2.26(s,3H),2.04(d,J＝10.9Hz,3H),1.86-1.73(m,2H),1.72-1.52(m,4H),1.31(s,6H).¹H NMR(300MHz,Chloroform-d)δ:8.71(s,1H),8.53(d,J＝4.0Hz,1H),7.77(d,J＝7.7Hz,1H),7.78–7.39(m,3H),7.30-7.23(m,1H),6.53(d,J＝15.6Hz,1H),6.07(d,J＝4.7Hz,1H),3.94(d,J＝7.5Hz,1H),3.59(s,2H),3.15(t,J＝6.0Hz,2H),2.92(d,J＝8.4Hz,2H),2.38–2.27(m,2H),2.23(s,3H),2.02(d,J＝10.9Hz,2H),1.83–1.70(m,2H),1.70–1.51(m,4H),1.29(s,6H).ESI-HRMS m/z calculated for C₃₃H₃₆N₃O₄[M+H]⁺538.27003,found 538.26974.

Example 7: (E) synthesis of (E) -3- (pyridin-3-yl) -N- ((1- ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) piperidin-4-yl) methyl) acrylamide (S7)

¹H NMR(300MHz,Chloroform-d)δ:8.72(s,1H),8.54(d,J＝4.1Hz,1H),7.77(d,J＝7.9Hz,1H),7.72–7.47(m,3H),7.35–7.26(m,1H),6.54(d,J＝15.7Hz,1H),6.14(s,1H),3.58(s,2H),3.30(t,J＝6.2Hz,2H),3.15(t,J＝6.1Hz,2H),2.97(d,J＝11.0Hz,2H),2.23(s,3H),2.17–2.02(m,3H),1.89–1.70(m,4H),1.69–1.59(m,2H),1.49–1.33(m,2H),1.29(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.8,175.9,165.5,160.9,150.5,150.3,150.1,149.3,144.6,137.5,134.5,133.6,130.8,127.5,126.6,123.8,123.0,120.7,120.4,119.3,53.1,52.5,45.3,38.0,35.9,34.8,32.0,30.0,29.9,19.3,9.2,8.8.ESI-HRMS m/z calculatedfor C₃₄H₃₈N₃O₄[M+H]⁺552.28568,found 552.28517.

Example 8: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (2- (4- ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthro [1,2-b ] furan-2-yl) methyl) piperidin-1-yl) ethyl) acrylamide (S8)

¹H NMR(300MHz,Chloroform-d)δ:8.73(s,1H),8.55(d,J＝4.7Hz,1H),7.78(d,J＝8.0Hz,1H),7.70–7.48(m,3H),7.33–7.27(m,1H),6.49(d,J＝15.7Hz,1H),6.32(s,1H),3.60(s,2H),3.49(d,J＝5.9Hz,2H),3.16(t,J＝6.6Hz,2H),2.57(s,10H),2.25(s,3H),1.92–1.70(m,2H),1.68–1.59(m,2H),1.29(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.8,175.9,165.2,160.8,150.5,150.3,150.0,149.4,144.6,137.5,134.4,133.5,130.8,127.4,126.6,123.8,123.0,120.6,120.5,119.3,56.6,52.9,52.7,52.2,38.0,36.2,34.8,32.0,30.0,19.3,9.2.ESI-HRMS m/z calculated for C₃₄H₃₉N₄O₄[M+H]⁺567.29658,found567.29639.

Example 9: (E) synthesis of (E) -3-pyridin-3-yl) -N- (2- (1- ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthro [1,2-b ] furan-2-yl) methyl) piperidin-4-yl) ethyl) acrylamide (S9)

¹H NMR(300MHz,Chloroform-d)δ:8.71(s,1H),8.53(d,J＝4.8Hz,1H),7.76(d,J＝7.6Hz,1H),7.67–7.54(m,3H),7.32–7.27(m,1H),6.51(d,J＝15.6Hz,1H),6.07(s,1H),3.65(s,2H),3.42(q,J＝6.4Hz,2H),3.15(t,J＝5.9Hz,2H),3.01(d,J＝10.6Hz,2H),2.24(s,3H),2.21–2.10(m,2H),1.94–1.71(m,4H),1.68–1.59(m,2H),1.58–1.49(m,2H),1.45–1.34(m,2H),1.29(s,6H).¹³C NMR(125MHz,Chloroform-d)δ:180.5,176.7,167.3,158.4,152.7,150.1,149.6,148.0,142.4,138.7,134.3,129.7,128.6,128.2,127.7,123.3,121.4,121.1,120.6,118.0,54.8,51.6,38.9,34.8,34.6,34.0,31.1,29.9,29.5,19.2,9.9.ESI-HRMS m/z calculated for C₃₅H₄₀N₃O₄[M+H]⁺566.30133,found 566.30073.

Example 10: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (4- ((((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) methyl) phenethyl) acrylamide (S10)

Example 11: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (4- ((((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) methyl) benzyl) acrylamide (S11)

¹H NMR(300MHz,DMSO-d₆)δ:8.76(d,J＝2.1Hz,1H),8.67(t,J＝6.0Hz,1H),8.61–8.51(m,1H),8.05–7.93(m,1H),7.78(d,J＝8.2Hz,1H),7.57–7.40(m,3H),7.36–7.20(m,4H),6.80(d,J＝15.9Hz,1H),4.38(d,J＝5.8Hz,2H),3.69(d,J＝4.3Hz,3H),3.04(d,J＝6.5Hz,2H),2.10(s,3H),1.78-1.64(m,2H),1.63-1.57(m,2H),1.27(s,6H).¹³C NMR(126MHz,DMSO)δ:182.6,175.0,164.4,159.1,152.5,150.1,149.1,149.1,142.8,138.8,137.6,135.6,133.9,133.4,130.6,128.0,127.2,126.7,126.4,124.1,123.9,120.0,119.9,116.3,51.5,41.9,37.4,34.3,31.5,29.4,18.7,8.5.ESI-HRMS m/z calculatedfor C₃₆H₃₆N₃O₄[M+H]⁺574.27003,found574.26966.

Example 12: (E) -3- (pyridin-3-yl) -N- (2- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthro [1,2-b ] furan-2-yl) methyl) amino) ethyl) acrylamide (S12)

¹H NMR(300MHz,Chloroform-d)δ:8.70(s,1H),8.52(d,J＝4.6Hz,1H),8.14(t,J＝5.0Hz,2H),7.93(d,J＝8.0Hz,1H),7.71(d,J＝8.2Hz,1H),7.52(d,J＝8.1Hz,1H),7.41(d,J＝15.0Hz,1H),7.42-7.40(m,1H),6.71(d,J＝15.9Hz,1H),3.76(s,2H),3.01(t,J＝5.5Hz,3H),2.66(t,J＝5.9Hz,3H),2.15(s,3H),1.77-1.62(m,2H),1.63-1.53(m,2H),1.23(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.6,175.9,165.5,160.8,151.7,150.5,150.4,149.3,144.7,137.5,134.5,133.6,130.8,127.3,126.5,123.8,122.9,120.5,120.4,117.7,48.0,43.2,39.3,37.9,34.8 32.0,30.0,19.2,8.9.ESI-HRMS m/z calculated for C₃₀H₃₂N₃O₄[M+H]⁺498.23873,found 498.23819.

Example 13: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (2- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) propyl) acrylamide (S13)

Example 14: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (2- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) butyl) acrylamide (S14)

¹H NMR(300MHz,Chloroform-d)δ:8.68(s,1H),8.52(d,J＝3.8Hz,1H),7.72(d,J＝8.1Hz,1H),7.62–7.46(m,3H),7.25–7.22(m,1H),6.71(s,1H),6.47(d,J＝15.7Hz,1H),3.83(s,2H),3.41(q,J＝6.0Hz,2H),3.13(t,J＝6.3Hz,2H),2.79–2.65(m,2H),2.23(s,3H),1.90–1.72(m,1H),1.73–1.58(m,6H),1.27(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.2,175.6,165.7,161.4,150.8,150.2,149.1,144.8,136.9,134.5,133.7,130.9,126.9,126.5,123.8,123.4,120.7,120.3,48.0,42.6,39.3,37.9,34.8,31.9,30.0,27.1,25.8,19.2,9.2.ESI-HRMS m/z calculated for C₃₂H₃₆N₃O₄[M+H]⁺526.27003,found526.26987.

Example 15: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (2- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) pentyl) acrylamide (S15)

¹H NMR(300MHz,Chloroform-d)δ:8.71(d,J＝1.8Hz,1H),8.54(dd,J＝4.8,1.4Hz,1H),7.76(dt,J＝8.0,2.0Hz,1H),7.64–7.52(m,3H),7.33–7.27(m,1H),6.48(d,J＝15.7Hz,1H),6.05(t,J＝4.8Hz,1H),3.80(s,2H),3.39(q,J＝6.6Hz,2H),3.15(t,J＝6.3Hz,2H),2.65(t,J＝6.9Hz,2H),2.23(s,3H),1.85–1.70(m,2H),1.71–1.51(m,6H),1.50–1.36(m,2H),1.29(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.7,175.9,165.3,160.7,151.9,150.4,150.3,149.3,144.6,137.3,134.4,133.6,130.8,127.4,126.5,123.8,123.1,120.5,120.5,117.7,48.9,43.6,39.8,38.0,34.8,32.0,30.0,30.0,29.5,24.9,19.2,9.0.ESI-HRMS m/z calculated for C₃₃H₃₈N₃O₄[M+H]⁺540.28568,found 540.28540.

Example 16: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (2- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) hexyl) acrylamide (S16)

¹H NMR(300MHz,Chloroform-d)δ:8.73(d,J＝2.2Hz,1H),8.55(dd,J＝4.8,1.6Hz,1H),7.78(dt,J＝7.9,2.0Hz,1H),7.66–7.52(m,3H),7.29(dd,J＝8.2,5.1Hz,1H),6.49(d,J＝15.7Hz,1H),5.93(t,J＝5.0Hz,2H),3.80(s,2H),3.38(q,J＝6.7Hz,2H),3.15(t,J＝6.3Hz,2H),2.64(t,J＝7.1Hz,2H),2.23(s,3H),1.85–1.69(m,2H),1.69–1.48(m,6H),1.46–1.32(m,4H),1.29(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.7,175.9,165.3,160.7,152.1,150.3,150.2,149.2,144.6,137.1,134.4,133.6,130.9,127.4,126.5,123.8,123.3,120.5,120.5,117.5,49.0,43.6,39.8,37.9,34.8,31.9,30.0,29.8,29.7,27.0,26.9,19.2,8.9.

ESI-HRMS m/z calculated for C₃₄H₄₀N₃O₄[M+H]⁺554.30130,found 554.30102.

Example 17: synthesis of N- (1- ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthro [1,2-b ] furan-2-yl) methyl) piperidin-4-yl) imidazo [1,2-a ] pyridine-6-carboxamide (S17)

¹H NMR(300MHz,Chloroform-d)δ:8.81(s,1H),7.65(s,1H),7.62(s,1H),7.60–7.52(m,3H),7.42(dd,J＝9.5,1.8Hz,1H),6.47(d,J＝7.8Hz,1H),4.10–3.94(m,1H),3.60(s,2H),3.14(t,J＝6.3Hz,2H),2.96(d,J＝11.4Hz,2H),2.31(t,J＝10.8Hz,2H),2.23(s,3H),2.06(d,J＝12.2Hz,2H),1.82–1.59(m,6H),1.29(s,6H).¹³C NMR(126MHz,CDCl3)δ:183.7,175.9,164.4,160.9,150.4,150.0,145.5,144.6,135.1,133.6,128.0,127.4,126.5,122.1,120.6,120.5,120.4,119.3,117.2,113.7,52.3,52.2,47.2,37.9,34.8,32.1,31.9,30.0,19.2,9.2.ESI-HRMS m/z calculated for C₃₃H₃₅N₄O₄[M+H]⁺551.26532,found 551.26531

Example 18: 2- ((4- (imidazo [1,2-a ] pyridin-6-oyl) piperazin-1-yl) methyl) -1,6, 6-trimethyl-6, 7,8, 9-hexahydrophenanthrene [1,2-b ] furan-10, 11-dione

¹H NMR(300MHz,Chloroform-d)δ:8.36(t,J＝1.3Hz,1H),7.68(d,J＝1.2Hz,1H),7.62(d,J＝2.5Hz,2H),7.62–7.53(m,2H),7.15(dd,J＝9.3,1.7Hz,1H),3.68(s,4H),3.63(s,2H),3.16(t,J＝6.3Hz,2H),2.57(t,J＝4.9Hz,4H),2.24(s,3H),1.83–1.74(m,2H),1.73–1.60(m,2H),1.30(s,6H).¹³C NMR(126MHz,CDCl3)δ:183.6,175.9,167.3,160.9,150.5,149.4,145.0,144.7,135.0,133.5,127.3,126.7,126.7,123.3,121.3,120.6,120.4,119.6,117.6,113.4,52.7,52.2,38.0,34.8,32.0,30.0,19.2,9.1.ESI-HRMS m/zcalculated for C₃₂H₃₃N₄O₄[M+H]⁺537.24963,found 537.24951.

Example 19: synthesis of N- (2- (4- ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10,11-6,7,8, 9-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) piperazin-1-yl) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide (S19)

¹H NMR(300MHz,Chloroform-d)δ:8.83(s,1H),7.68(s,1H),7.65(s,1H),7.63–7.54(m,3H),7.39(dd,J＝9.4,1.8Hz,1H),3.63–3.52(m,4H),3.16(t,J＝6.3Hz,2H),2.70–2.50(m,10H),2.24(s,3H),1.90–1.71(m,2H),1.72–1.57(m,2H),1.29(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.7,175.9,164.8,160.8,150.3,150.0,145.6,144.6,135.2,133.5,128.0,127.4,126.6,121.8,120.6,120.5,120.3,119.2,117.3,113.7,56.5,52.9,52.3,38.0,36.6,34.8,32.0,30.0,19.2,9.1.ESI-HRMS m/z calculated for C₃₄H₃₈N₅O₄[M+H]⁺580.29183,found 580.29154.

Example 20: n- ((1- ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthro [1,2-b ] furan-2-yl) methyl) piperidin-4-yl) methyl) imidazo [1,2-a ] pyridine-6-carboxamide (S20)

¹H NMR(300MHz,Chloroform-d)δ:8.85(s,1H),7.70–7.52(m,5H),7.44(d,J＝9.4Hz,1H),6.70(s,1H),3.63(s,2H),3.38(t,J＝6.1Hz,2H),3.15(t,J＝6.1Hz,2H),3.02(d,J＝11.0Hz,2H),2.23(s,3H),2.14(d,J＝11.1Hz,2H),1.87–1.71(m,4H),1.70–1.60(m,3H),1.59–1.38(m,2H),1.29(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.6,175.7,165.1,161.0,150.3,149.4,145.4,144.5,134.9,133.5,127.9,127.2,126.4,122.3,120.6,120.4,120.3,119.6,117.0,113.6,52.9,52.2,45.4,37.8,35.5,34.7,31.8,29.9,29.6,19.1,9.1.ESI-HRMS m/z calculated for C₃₄H₃₇N₄O₄[M+H]⁺565.28093,found 565.28037.

Example 21: synthesis of N- (2- (1- ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl)) piperidin-4-yl) methyl) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide (S21)

¹H NMR(300MHz,Chloroform-d)δ:8.84(s,1H),7.75–7.52(m,5H),7.42(d,J＝9.5Hz,1H),6.51(s,1H),3.63(s,2H),3.50(q,J＝6.5Hz,2H),3.15(t,J＝6.0Hz,2H),3.00(d,J＝10.4Hz,2H),2.24(s,3H),2.14(t,J＝9.5Hz,2H),1.88–1.71(m,4H),1.69–1.51(m,4H),1.40(s,3H),1.29(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.6,175.8,164.8,160.9,150.3,145.4,144.5,135.1,133.5,127.9,127.3,126.5,121.8,120.6,120.3,117.2,113.6,53.3,52.3,37.9,37.9,36.2,34.7,33.1,31.9,31.7,29.9,19.1,9.1.ESI-HRMS m/zcalculated for C₃₅H₃₉N₄O₄[M+H]⁺579.29658,found 579.29641.

Example 22: synthesis of N- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) benzyl) imidazo [1,2-a ] pyridine-6-carboxamide (S22)

¹H NMR(300MHz,DMSO-d₆)δ:9.11(s,1H),8.97–8.91(m,1H),8.03(s,1H),7.77(d,J＝2Hz,1H),7.70–7.63(m,2H),7.62–7.53(m,2H),7.50(d,J＝8.1Hz,1H),7.10(d,J＝8.2Hz,2H),6.66(d,J＝8.3Hz,2H),6.12(t,J＝6.1Hz,5H),4.32(dd,J＝11.0,5.8Hz,4H),3.04(t,J＝6.1Hz,2H),2.21(s,3H),1.81–1.64(m,2H),1.64–1.53(m,2H),1.25(s,6H).¹³CNMR(126MHz,DMSO)δ:182.4,175.0,163.9,159.0,151.7,149.1,147.1,142.8,134.3,133.3,128.4,128.3,127.0,126.6,126.4,122.8,120.0,119.8,119.7,116.1,116.0,114.2,112.2,42.4,37.8,37.4,34.3,31.4,29.42 18.7,8.5.ESI-HRMS m/z calculatedfor C₃₅H₃₃N₄O₄[M+H]⁺573.24963,found573.24972.

Example 23: synthesis of N- (2- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) ethyl) imidazo [1,2-a ] pyridine-6-carboxamide (S23)

¹H NMR(300MHz,Chloroform-d)δ:8.80(s,1H),7.65(s,1H),7.61(s,1H),7.60–7.47(m,2H),7.44-7.42(m,2H),7.18(s,1H),3.89(s,2H),3.63(d,J＝6.0Hz,2H),3.11(t,J＝6.3Hz,2H),3.00(t,J＝6.0Hz,2H),2.22(s,3H),1.82–1.69(m,2H),1.68–1.56(m,2H),1.28(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.5,175.8,165.0,160.9,150.6,145.5,144.8,135.2,133.5,128.0,127.1,126.5,122.1,120.4,120.3,120.3,117.2,113.7,47.7,43.0,39.4,37.9,34.8,31.9,30.0,19.2,9.0.ESI-HRMS m/z calculated for C₃₀H₃₁N₄O₄[M+H]⁺511.23398,found 511.23343.

Example 24: synthesis of N- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) butyl) -1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxamide (S24)

¹H NMR(5300MHz,Chloroform-d)δ:8.66(d,J＝1.8Hz,1H),8.42(dd,J＝5.7,1.8Hz,1H),7.50(d,J＝8.4Hz,1H),7.39–7.33(m,2H),6.50(t,J＝4.3Hz,1H),4.86(s,1H),4.40(d,J＝13.5Hz,1H),4.30(d,J＝13.5Hz,1H),4.01(d,J＝5.9Hz,2H),3.18(td,J＝6.3,4.4Hz,2H),3.13–3.07(m,2H),2.73(td,J＝6.3,4.2Hz,2H),2.51(tt,J＝5.9,4.1Hz,1H),2.25(s,2H),1.79–1.71(m,2H),1.66–1.60(m,2H),1.58–1.49(m,4H),1.31(s,6H).¹³C NMR(125MHz,Chloroform-d)δ:180.5,176.8,158.6,158.1,153.6,148.0,145.9,145.6,143.1,142.3,132.6,128.6,128.2,127.7,121.4,118.3,116.9,114.4,52.4,52.1,48.3,46.1,39.4,39.0,34.8,31.1,29.5,26.4,26.0,19.2,9.9.ESI-HRMS m/z calculated forC₃₂H₃₇N₄O₄[M+H]⁺541.28093,found 541.28102.

Example 25: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (2- (((1,6, 6-trione-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) ((1,9, 9-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) ethyl) acrylamide (S25)

¹H NMR(300MHz,Chloroform-d)δ:8.67(s,1H),8.56(d,J＝3.7Hz,1H),7.71(d,J＝9.7Hz,1H),7.57(d,J＝15.7Hz,1H),7.54–7.33(m,4H),7.32–7.27(m,1H),6.47(d,J＝15.7Hz,1H),6.38(s,1H),3.81(s,2H),3.60(q,J＝5.6Hz,2H),3.09(t,J＝6.3Hz,4H),2.89(t,J＝5.9Hz,2H),2.27(s,6H),1.82–1.69(m,4H),1.67–1.56(m,4H),1.26(s,12H).¹³C NMR(126MHz,Chloroform-d)δ:183.1,175.6,165.2,160.7,150.6,150.6,150.4,149.3,144.8,137.6,134.4,133.6,130.6,127.1,126.5,123.8,122.8,120.5,120.1,119.0,52.6,48.4,37.9,37.4,34.8,31.9,30.0,19.2,9.2.ESI-HRMS m/z calculated for C₅₀H₅₀N₃O₇[M+H]⁺804.36433,found 804.36422.

Example 26: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (2- (((1,6, 6-trione-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) ((1,9, 9-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) propyl) acrylamide (S26)

¹H NMR(300MHz,Chloroform-d)δ:8.55–8.47(m,2H),7.56–7.40(m,3H),7.40–7.28(m,4H),7.13(dd,J＝7.9,4.8Hz,1H),6.36(d,J＝15.7Hz,1H),3.78(s,4H),3.52(q,J＝6.0Hz,2H),3.06(t,J＝6.3Hz,4H),2.81(t,J＝5.9Hz,2H),2.28(s,6H),1.92(t,J＝6.2Hz,2H),1.87–1.66(m,4H),1.63–1.48(m,4H),1.16(s,12H).¹³C NMR(126MHz,CDCl₃)δ:183.1,175.5,165.0,160.8,150.7,150.3,149.4,144.7,136.8,133.8,133.5,130.6,126.8,126.4,126.4,123.7,123.3,120.4,120.3,119.5,53.2 48.6,39.6,37.8,34.7,31.8,30.0,26.1,19.1,9.2.ESI-HRMS m/z calculated for C₅₀H₅₀N₃O₇[M+H]⁺818.37998,found 818.37966.

Example 27: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (2- (((1,6, 6-trione-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) ((1,9, 9-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) butyl) acrylamide (S27)

¹H NMR(300MHz,Chloroform-d)δ:8.66(s,1H),8.52(d,J＝4.7Hz,1H),7.76–7.66(m,1H),7.64–7.49(m,3H),7.38(d,J＝8.1Hz,2H),7.25–7.21(m,1H),6.54–6.42(m,2H),3.73(s,4H),3.52–3.37(m,2H),3.09(t,J＝6.3Hz,4H),2.64(t,J＝6.4Hz,2H),2.26(s,6H),1.83–1.56(m,12H),1.27(s,12H).¹³C NMR(126MHz,CDCl₃)δ:183.0,175.4,165.2,160.5,150.5,150.3,150.3,149.2,144.5,137.1,134.2,133.5,130.7,127.0,126.2,123.6,123.1,120.4,120.2,118.8,54.2,48.5,39.7,37.8,34.7,31.8,29.9,27.6,25.0,19.1,9.1.ESI-HRMS m/z calculated for C₅₂H₅₄N₃O₇[M+H]⁺832.39563,found 832.39515.

Example 28: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (2- (((1,6, 6-trione-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) ((1,9, 9-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) pentyl) acrylamide (S28)

¹H NMR(300MHz,Chloroform-d)δ:8.69(s,1H),8.53(d,J＝4.2Hz,1H),7.77(d,J＝7.9Hz,1H),7.65–7.50(m,1H),7.40(d,J＝8.1Hz,1H),7.31–7.27(m,1H),6.48(d,J＝15.6Hz,1H),6.02(t,J＝5.8Hz,1H),3.70(s,4H),3.39(q,J＝6.7Hz,2H),3.08(t,J＝6.3Hz,4H),2.60(t,J＝7.0Hz,2H),2.25(s,6H),1.82–1.70(m,4H),1.69–1.54(m,8H),1.45(q,J＝7.5Hz,2H),1.29(s,12H).¹³C NMR(126MHz,CDCl₃)δ:183.2,175.6,165.3,160.5,151.0,150.4,149.2144.5,137.3,137.3,134.4,133.6,130.8,127.1,126.3,123.8,123.1,123.1,120.6,120.3,118.6,54.1,48.6,39.9,37.9,34.8,31.9,30.0,29.5,26.9,24.5,19.2,9.1.ESI-HRMS m/z calculated for C₅₃H₅₆N₃O₇[M+H]⁺846.41128,found 846.41101.

Example 29: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (2- (((1,6, 6-trione-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) ((1,9, 9-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) hexyl) acrylamide (S29)

¹H NMR(300MHz,Chloroform-d)δ8.73(s,1H),8.54(d,J＝4.5Hz,1H),7.80(d,J＝7.9Hz,1H),7.68–7.51(m,3H),7.41(d,J＝8.1Hz,2H),7.36–7.27(m,1H),6.53(d,J＝15.7Hz,1H),5.98(t,J＝5.7Hz,1H),3.70(s,4H),3.37(q,J＝6.8Hz,2H),3.10(t,J＝6.3Hz,4H),2.58(t,J＝7.3Hz,2H),2.25(s,6H),1.87–1.69(m,4H),1.68–1.51(m,8H),1.45–1.34(m,4H),1.30(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.2,175.6,165.3,160.4,151.1,150.4,150.3,149.3,144.5,137.3,134.4,133.6,130.9,127.2,126.3,123.8,123.2,120.6,120.3,118.6,54.4,48.7,39.9,37.9,34.8,31.9,30.0,29.8,27.3,27.0,26.9,19.2,9.1.ESI-HRMS m/z calculated for C₅₄H₅₈N₃O₇[M+H]⁺860.42693,found860.42668.

Example 30: (E) -2,2' - (((4- (3- (pyridin-3-yl) acryloyl) benzyl) azane) bis (methylene)) bis (1,6, 6-trimethyl-6, 7,8, 9-tetrahydrophenanthrene [1,2-b ] furan-10, 11-dione)

¹H NMR(300MHz,Chloroform-d)δ:8.78(s,1H),8.56(dd,J＝4.8,1.6Hz,1H),8.29(s,1H),7.87(d,J＝8.0Hz,1H),7.76–7.65(m,3H),7.59(d,J＝8.1Hz,2H),7.45(d,J＝8.1Hz,2H),7.37(d,J＝8.2Hz,2H),7.30(dd,J＝8.0,4.9Hz,1H),6.82(d,J＝15.6Hz,1H),3.75(s,6H),3.10(t,J＝5.9Hz,4H),2.21(s,6H),1.86–1.69(m,4H),1.70–1.56(m,4H),1.30(s,12H).¹³C NMR(126MHz,CDCl₃)δ:183.3,175.6,163.6,160.6,151.0,150.4,150.4,149.3,144.6,138.4,137.7,134.8,134.4,133.7,130.9,129.5,127.2,126.3,123.9,123.7,120.6,120.3,120.1,118.8,58.5,48.5,37.9,34.8,31.9,30.1,19.2,9.1.ESI-HRMSm/z calculated for C₅₅H₅₂N₃O₇[M+H]⁺866.37998,found 866.37952.

Example 31: (E) synthesis of (E) -N- (4- ((bis ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) methyl) benzyl) -3- (pyridin-3-yl) acrylamide (S31)

¹H NMR(300MHz,Chloroform-d)δ:8.76(s,1H),8.56(d,J＝4.8Hz,1H),7.87(d,J＝8.1Hz,1H),7.71–7.57(m,3H),7.46(d,J＝8.1Hz,2H),7.35–7.28(m,3H),7.24–7.19(m,2H),6.60(d,J＝15.7Hz,1H),6.14(t,J＝5.8Hz,1H),4.52(d,J＝5.7Hz,2H),3.75(s,6H),3.10(t,J＝6.0Hz,4H),2.17(s,6H),1.89–1.69(m,4H),1.71–1.58(m,4H),1.41–1.15(m,12H).¹³C NMR(126MHz,CDCl₃)δ:183.4,175.6,165.3,160.4,150.8,150.4,149.4,144.6,137.9,137.6,137.5,134.5,133.7,130.9,128.9,128.0,127.2,126.3,123.8,123.1,120.5,120.2,118.8,58.8,48.9,43.6,37.9,34.8,31.9,30.0,19.2,9.1.ESI-HRMS m/zcalculated for C₅₆H₅₄N₃O₇[M+H]⁺880.39563,found 880.39484.

Example 32: (E) synthesis of (E) -1,6, 6-trimethyl-2- (((4- (1- (3- (pyridin-3-yl) acryloyl) piperidin-4-yl) phenyl) amino) methyl) -6,7,8, 9-tetrahydrophenanthrene [1,2-b ] furan-10, 11-dione (S32)

The method comprises the following steps: (E) synthesis of (E) -N- (4- (piperidin-4-yl) phenyl) -3- (pyridin-3-yl) acrylamide (11a)

(E) -3- (3-pyridine) acrylic acid 3(500mg, 3.35mmol) was weighed, dissolved in anhydrous DMF (10mL), EDCI (1.1g, 5.7mmol), HOBt (595mg, 4.4mmol), TEA (0.92mL,6.7mmol) and compound 10a (589.6mg, 3.35mmol) were added successively, the reaction was stirred at room temperature for 5h, stopped, and DMF was spin-dried under reduced pressure. 5ml of saturated NaHCO was added to the reaction residue₃Solution, DCM (20 ml. times.3), combined organic phases, saturated NH₄Washed 1 time with Cl (10ml) and with saturated brine (10ml)1 time, drying by anhydrous sodium sulfate, filtering, evaporating the solvent to dryness, preparing sand, and separating and purifying by column chromatography (DCM: MeOH: 60: 1-20: 1) to obtain 11a 926mg (90%) of a light yellow solid.¹H NMR(300MHz,DMSO-d6)δ:8.88(d,J＝2.1Hz,1H),8.54(dd,J＝4.8,1.5Hz,1H),8.20(d,J＝8.1Hz,1H),7.60–7.36(m,3H),6.88(d,J＝8.2Hz,2H),6.49(d,J＝8.2Hz,2H),4.87(s,2H),4.52(dd,J＝62.9,13.2Hz,2H),3.13(t,J＝12.8Hz,1H),2.81–2.55(m,2H),1.76(t,J＝10.0Hz,2H),1.59–1.32(m,2H).¹³C NMR(75MHz,DMSO)δ163.9,150.0,149.5,146.7,137.8,134.4,132.9,131.0,127.0,123.8,120.7,114.1,45.8,42.5,41.1,34.4.

Step three: (E) synthesis of (E) -1,6, 6-trimethyl-2- (((4- (1- (3- (pyridin-3-yl) acryloyl) piperidin-4-yl) phenyl) amino) methyl) -6,7,8, 9-tetrahydrophenanthrene [1,2-b ] furan-10, 11-dione (S32)

To hydrochloride salt 11a (92mg, 0.30mmol) was added DMF (5mL), K₂CO₃(124mg,0.90mmol), TEA (0.083mL, 0.60mmol) and Compound 2(100mg, 0.30mmol) were heated to 60 ℃ and stirred for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, DMF was spin-dried under reduced pressure, and DCM (10mL) was added to dissolve the DMF, the DMF was washed with water 1 time (5mL), saturated brine was washed with water 1 time (5mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, prepared into sand, and separated and purified by column chromatography (DCM: MeOH 60: 1-40: 1) to obtain S32(85mg, 46%) as a red solid.

¹H NMR(300MHz,Chloroform-d)δ:8.76(s,1H),8.56(d,J＝4.8Hz,1H),7.82(d,J＝8.0Hz,1H),7.74–7.43(m,3H),7.37–7.27(m,1H),7.11–6.96(m,3H),6.67(d,J＝8.0Hz,2H),4.86(d,J＝13.0Hz,1H),4.30(s,2H),4.21(d,J＝15.0Hz,2H),3.34–2.98(m,3H),2.73(q,J＝12.8,11.7Hz,2H),2.27(s,3H),2.01–1.86(m,2H),1.81–1.71(m,2H),1.69–1.57(m,4H),1.29(s,6H).¹³C NMR(126MHz,Chloroform-d)δ:183.6,175.8,164.8,160.9,150.7,150.3,150.3,149.3,146.0,144.6,138.9,135.2,134.4,133.5,131.3,127.7,127.3,126.6,123.8,120.6,120.3,119.9,117.8,113.5,46.9,43.3,42.0,39.4,37.9,34.8,34.5,33.3,32.0,30.0,19.2,9.0.ESI-HRMS m/z calculated for C₃₉H₄₀N₃O₄[M+H]⁺614.30133,found 614.30118.

The compounds S33 to S34 in examples 33 and 34 below were all obtained by the synthesis method of example 32, and the corresponding starting materials were replaced.

Example 33: (E) synthesis of (E) -3- (pyridin-3-yl) -N- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) phenethyl) acrylamide (S33)

Example 34: (E) synthesis of (E) -N- (2- (phenyl ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b furan-2-yl) methyl) amino) ethyl) -3- (pyridin-3-yl) a-acrylamide (S34)

¹H NMR(300MHz,Chloroform-d)δ:8.63(s,1H),8.51(d,J＝4.7Hz,1H),7.72(d,J＝7.9Hz,1H),7.62–7.47(m,2H),7.37(d,J＝8.2Hz,1H),7.30-7.21(m,2H),6.93(d,J＝8.1Hz,2H),6.79(t,J＝7.3Hz,1H),6.64–6.43(m,2H),4.48(s,2H),3.66(s,4H),3.03(s,2H),2.22(s,3H),1.79–1.65(m,2H),1.64–1.54(m,2H),1.23(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.4,175.7,165.6,160.8,150.6,150.5,149.2,148.2,144.7,137.5,134.5,133.6,130.7,129.6,127.2,126.4,123.8,122.7,120.4,120.3,118.8,118.1,114.4,50.4,47.0,37.9,37.7,34.8,31.9,30.0,19.2,8.9.ESI-HRMS m/z calculated for C₃₆H₃₆N₃O₄[M+H]⁺574.27003,found 574.26961.

Example 35: (E) synthesis of (E) -N- (2- (ethyl ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) ethyl) -3- (piperidin-3-yl) acrylamide (S35)

The method comprises the following steps: (E) synthesis of (E) -N- (3- (ethylamino) ethyl) -3- (pyridin-3-yl) acrylamide (13a)

(E) -3- (3-pyridine) acrylic acid 3(500mg, 3.35mmol) was weighed out, dissolved in anhydrous DMF (10mL), EDCI (1.1g, 5.7mmol) and NHS (771mg, 6.7mmol) were added in this order, and the mixture was stirred at room temperature overnight. The reaction was stopped and DMF was spin-dried under reduced pressure. The reaction residue was dissolved in 20ml of ethyl acetate, washed with water (5ml) 1 time, washed with saturated brine (5ml) 1 time, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and dried under vacuum to give an NHS-activated active ester. The above active ester was dissolved in anhydrous DCM (10mL), DMAP (818.5mg, 6.7mmol) and compound 12a (1mL, 3.35mmol) were added, and the reaction was stirred at room temperature overnight. The reaction was stopped and 20mL DCM was added to dilute the reaction and saturated NaHCO₃Washing with a saturated ammonium chloride solution and washing with a saturated brine.¹H NMR(300MHz,Methanol-d4)δ:8.65(s,1H),8.46(d,J＝4.4Hz,1H),8.03(dd,J＝8.1,1.7Hz,1H),7.53(d,J＝16.0Hz,1H),7.42(dd,J＝8.1,4.8Hz,1H),6.75(d,J＝15.8Hz,1H),3.58(t,J＝5.9Hz,2H),3.13(t,J＝5.9Hz,2H),3.03(q,J＝7.2Hz,2H),1.26(t,J＝7.3Hz,3H).¹³C NMR(75MHz,Methanol-d4)δ:167.4,149.6,148.5,136.9,134.9,131.3,124.2,122.9,47.2,46.8,42.9,36.2,10.4.

Step three: (E) synthesis of (E) -N- (2- (ethyl ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) ethyl) -3- (piperidin-3-yl) acrylamide (S35)

To hydrochloric acid 13a (66mg, 0.30mmol) was added DMF (5mL), K₂CO₃(124mg,0.90mmol), TEA (0.083mL, 0.60mmol) and Compound 2(100mg, 0.30mmol) were heated to 60 ℃ and stirred for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature, DMF was spin-dried under reduced pressure, and DCM (10mL) was added to dissolve the DMF, the DMF was washed with water 1 time (5mL), saturated brine was washed with water 1 time (5mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, prepared into sand, and separated and purified by column chromatography (DCM: MeOH 60: 1-40: 1) to obtain S32(102mg, 65%) as a red solid.

¹H NMR(300MHz,Chloroform-d)δ:8.69(s,1H),8.56(d,J＝4.2Hz,1H),7.74(d,J＝7.6Hz,1H),7.58(d,J＝15.6Hz,1H),7.50(s,2H),7.31–7.27(m,1H),6.46(d,J＝15.6Hz,1H),3.70(s,2H),3.52(q,J＝5.6Hz,2H),3.11(t,J＝6.3Hz,2H),2.75(t,J＝5.8Hz,2H),2.66(q,J＝7.2Hz,2H),2.26(s,3H),1.75(q,J＝5.7Hz,2H),1.67–1.56(m,2H),1.23(s,6H),1.15(t,J＝7.1Hz,3H).¹³C NMR(126MHz,CDCl₃)δ:183.6,175.8,165.2,160.8,151.0,150.5,150.4,149.3,144.7,137.4,134.3,133.5,130.7,127.3,126.6,123.8,122.9,120.4,120.2,118.8,51.8,47.9,47.1,37.9,37.3,34.8,31.9,30.0,19.2,12.1,9.1.ESI-HRMS m/z calculated for C₃₂H₃₆N₃O₄[M+H]⁺526.27003found 526.26997.

The compounds S36 to S40 in examples 36 to 40 were obtained by the synthesis method of example 35, and the corresponding starting materials were replaced.

Example 36: (E) synthesis of (E) -N- (2- (methyl ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) ethyl) -3- (piperidin-3-yl) acrylamide (S36)

¹H NMR(300MHz,Chloroform-d)δ:8.72(s,1H),8.56(d,J＝4.7Hz,1H),7.75(s,1H),7.60(d,J＝15.8Hz,1H),7.51(s,2H),7.29(dd,J＝7.9,4.9Hz,1H),6.50(d,J＝15.8Hz,1H),6.67–6.39(m,1H),3.66(s,2H),3.57(q,J＝5.6Hz,2H),3.16(t,J＝6.3Hz,2H),2.71(t,J＝5.9Hz,2H),2.37(s,3H),2.28(s,3H),1.78(q,J＝5.4Hz,2H),1.63–1.58(m,2H),1.27(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.6,175.9,165.3,160.9,150.5,150.3,149.3,144.7,137.4,134.5,133.5,130.8,127.3,126.6,123.8,123.0,120.4,120.3,119.2,55.1,51.1,41.9,37.9,37.0,34.8,31.9,30.0,19.2,9.1.ESI-HRMS m/zcalculated for C₃₁H₃₄N₃O₄[M+H]⁺512.25438,found 512.25414.

Example 37: (E) synthesis of (E) -N- (2- (methyl ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) propyl) -3- (piperidin-3-yl) acrylamide (S37)

¹H NMR(300MHz,Chloroform-d)δ:8.68(d,J＝2.2Hz,1H),8.56(dd,J＝4.8,1.6Hz,1H),7.73(dt,J＝8.0,2.0Hz,1H),7.57(d,J＝15.7Hz,1H),7.54–7.46(m,2H),7.34–7.26(m,2H),6.52–6.37(m,2H),3.70(s,2H),3.51(q,J＝5.6Hz,2H),3.11(t,J＝6.3Hz,2H),2.75(t,J＝6.0Hz,2H),2.52(t,J＝7.4Hz,2H),2.26(s,3H),1.85–1.69(m,2H),1.70–1.51(m,4H),1.24(s,6H),0.93(t,J＝7.3Hz,3H).¹³C NMR(126MHz,CDCl₃)δ:183.6,175.8,165.1,160.8,150.5,150.4,149.4,144.8,137.4,134.3,133.5,130.7,127.3,126.6,123.8,122.9,120.4,120.2,56.0,52.5,47.5,37.9,37.3,34.8,31.9,30.0,20.4,19.2,11.9,9.1.ESI-HRMS m/z calculated for C₃₃H₃₈N₃O₄[M+H]⁺540.28568,found 540.28526.

Example 38: (E) synthesis of (E) -N- (2- ((2-hydroxyethyl) ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) ethyl) -3- (pyridin-3-yl) acrylamide (S38)

¹H NMR(300MHz,DMSO-d₆)δ:8.65(d,J＝2.2Hz,1H),8.53(dd,J＝4.8,1.6Hz,1H),8.04(t,J＝5.5Hz,1H),7.88(dt,J＝8.0,2.0Hz,1H),7.70(d,J＝8.2Hz,1H),7.53(d,J＝8.2Hz,1H),7.45–7.32(m,2H),6.67(d,J＝15.9Hz,1H),4.49(t,J＝5.4Hz,1H),3.75(s,2H),3.53(q,J＝5.8Hz,2H),3.31–3.25(m,2H),2.95(t,J＝6.5Hz,2H),2.64(t,J＝6.2Hz,4H),2.17(s,3H),1.77–1.61(m,2H),1.61–1.51(m,2H),1.23(s,6H).¹³C NMR(126MHz,DMSO-d₆)δ:182.6,175.0,164.4,159.3,151.5,150.0,149.1,148.9,142.7,135.0,133.7,133.3,130.6,126.6,126.3,124.1,123.8,119.9,119.8,117.3,59.1,56.2,53.0,47.8,37.3,34.2,31.4,29.3,18.6,8.6.ESI-HRMS m/z calculated for C₃₂H₃₆N₃O₅[M+H]⁺542.26495,found 542.26481.

Example 39: (E) -N- (2- (isopropyl ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) ethyl) -3- (pyridin-3-yl) acrylamide (39)

¹H NMR(300MHz,Chloroform-d)δ:8.61(s,1H),8.54(d,J＝4.7Hz,1H),7.68(d,J＝8.3Hz,1H),7.57–7.44(m,3H),7.3-7.2(m,1H),6.36(d,J＝15.7Hz,1H),3.64(s,2H),3.53–3.39(m,2H),3.12-2.97(m,3H),2.75(s,2H),2.26(s,3H),1.73(q,J＝5.8Hz,2H),1.65–1.55(m,2H),1.20(s,6H),1.11(d,J＝6.6Hz,6H).¹³C NMR(126MHz,CDCl₃)δ:183.5,175.8,165.1,160.7,150.5,150.4,149.4,144.8,137.3,134.2,133.5,130.6,127.3,126.5,123.8,122.8,120.6,120.1,51.4,48.0,44.3,37.9,37.6,34.7,31.9,30.0,19.2,18.4,9.0.ESI-HRMS m/z calculated for C₃₃H₃₈N₃O₄[M+H]⁺540.28568,found 540.28571.

Example 40: (E) -N- (2- (benzyl ((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) ethyl) -3- (pyridin-3-yl) acrylamide

¹H NMR(300MHz,Chloroform-d)δ:8.67(s,1H),8.55(d,J＝4.9Hz,1H),7.71(d,J＝8.0Hz,1H),7.58–7.44(m,3H),7.34–7.17(m,5H),6.32(d,J＝16.1Hz,1H),6.05(s,1H),3.70(d,J＝8.9Hz,4H),3.48(q,J＝5.1Hz,2H),3.10(t,J＝6.1Hz,2H),2.77(t,J＝5.0Hz,2H),2.15(s,3H),1.82–1.68(m,2H),1.68–1.53(m,2H),1.23(s,6H).¹³C NMR(126MHz,CDCl₃)δ:183.5,175.8,165.1,160.8,150.94,150.4,150.4,149.2,144.7,138.6,137.2,134.4,133.6,130.8,129.0,128.7,127.7,127.3,126.5,123.8,123.0,120.4,120.2,118.9,58.7,52.4,47.7,37.9,37.4,34.8,31.9,30.0,19.2,9.1.ESI-HRMS m/zcalculated for C₃₇H₃₈N₃O₄[M+H]⁺588.28568,found 588.28543.

Example 41: synthesis of (Z) -2-cyano-1- (pyridin-4-yl) -3- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthrene [1,2-b ] furan-2-yl) methyl) amino) butyl) guanidine (41)

The method comprises the following steps: synthesis of methyl (Z) -N' -cyano-N- (pyridin-4-yl) aminomethylthiomethyl ester (16a)

NaH (500g,1.3mmol) was weighed, 10mL DMF was added, the suspension was stirred at 0 ℃ for 15min, then compound 14a (1g,1.1mmol) was slowly added dropwise to the suspension, and the reaction was stirred at room temperature for 30 min. Compound 16a (1.6g, 1.06mmol) was dissolved in 5mL DMF and added to the suspension and reacted overnight at room temperature. Washed 3 times with diethyl ether/petroleum ether (5: 1). Glacial acetic acid was added to adjust the pH to 8 at 0 deg.C, filtered and the filter cake was dried under vacuum to give 16a as a pale yellow solid (1.4g, 69%).¹H NMR(300MHz,DMSO-d₆)δ8.39(d,J＝6.0Hz,2H),7.46(d,J＝6.0Hz,2H),2.61(s,3H).¹³C NMR(75MHz,DMSO-d₆)δ:166.0,149.8,143.3,116.1,114.9,13.2.

Step two: synthesis of tert-butyl (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) butyl) carbamate (18a)

To 17a (199mg, 1.1mmol) was added DMF (8mL), TEA (0.083mL, 0.7mL) and Compound 2(300mg, 0.88mmol), and the mixture was heated to 45 ℃ and stirred for 1.5 h. After completion of the reaction, the reaction mixture was cooled to room temperature, DMF was spin-dried under reduced pressure, dissolved in DCM (10mL), washed with water 1 time (5mL), washed with saturated brine 1 time (5mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, prepared into sand, and separated and purified by column chromatography (DCM: MeOH ═ 60:1 to 20:1) to obtain a red solid 18a (196mg, 45%).¹H NMR(300MHz,Chloroform-d):δ7.53(d,J＝8.4Hz,1H),7.35(d,J＝8.4Hz,1H),4.03(d,J＝5.9Hz,2H),3.22–3.01(m,2H),3.10(t,J＝6.1Hz,2H),2.79(m,J＝2H),1.75-1.70(m,4H),1.68–1.54(m,4H),1.48(s,9H),1.31(s,6H).¹³C NMR(75MHz,Chloroform-d)δ180.6,176.8,158.6,157.2,153.6,148.0,142.3,128.5,128.2,127.7,121.4,118.2,114.5,79.7,48.2,46.4,40.0,39.1,34.8,30.9,29.5,28.3,27.0,26.0,19.2,9.8.

Step three: synthesis of (Z) -2-cyano-1- (pyridin-4-yl) -3- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthrene [1,2-b ] furan-2-yl) methyl) amino) butyl) guanidine (41)

Weighing 18a (150mg, 0.3mmol), adding 1mL ethyl acetate, adding 0.5mL HCl/ethyl acetate solution (3M) into the suspension, stirring at room temperature for 3h, directly filtering after the reaction is completed, washing the filter cake with ethyl acetate, and drying in vacuum to obtain hydrochloride, wherein the hydrochloride can be directly reacted in the next step without purification. The hydrochloride was dissolved in 10mL of pyridine, DMAP (37mg, 0.3mmol) and TEA (0.16mL, 1.2mmol) were added in this order, and the mixture was heated to 50 ℃ for overnight reaction. After the reaction, the reaction product is cooled to room temperature, pyridine is removed by spinning under reduced pressure, EA (20mL) is added for dissolution, washing is carried out once (10mL), saturated salt washing is carried out once (10mL), anhydrous sodium sulfate is dried, filtering is carried out, the solvent is evaporated to dryness, sand making is carried out, and column chromatography separation and purification (DCM: MeOH-60: 1-20: 1) are carried out to obtain a red solid 41.

¹H NMR(300MHz,DMSO-d)δ:9.04(s,1H),8.48–8.31(m,3H),7.80(t,J＝4.4Hz,1H),7.54(d,J＝8.4Hz,1H),7.39(d,J＝8.4Hz,1H),7.01(d,J＝6.1Hz,2H),4.02(d,J＝5.9Hz,2H),3.46(m,2H),3.16–3.01(m,2H),2.77(m,2H),2.25(s,3H),1.81–1.70(m,2H),1.67–1.59(m,4H),1.58–1.48(m,2H),1.31(s,6H).¹³C NMR(75MHz,DMSO)δ:180.5,176.8,158.6,154.8,153.6,149.8,148.0,145.1,142.3,128.6,128.2,127.7,121.4,118.3,118.0,114.4,112.8,48.3,46.1,41.2,39.0,34.8,31.1,29.5,26.4,26.0,19.2,9.2.

Example 42: synthesis of 1- (pyridin-4-yl-methyl) -3- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) phenyl) urea (S42)

The method comprises the following steps: synthesis of 4- (isocyanatomethyl) -pyridine (20a)

Compound 19a (300mg, 2.86mmol) was weighed out and dissolved in dry THF (5mL) under nitrogen and TEA (0.8mL, 5.72mmol) was added. Triphosgene (339mg, 1.14mmol) was dissolved in 3mL of anhydrous THF at 0 deg.C, added dropwise slowly to the above solution, transferred to room temperature, heated to 50 deg.C, and reacted overnight. After the reaction is completed, the solvent is removed by rotation under reduced pressure, and the mixture is directly put into the next reaction.

Step two: synthesis of tert-butyl (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) phenyl) carbamate (22a)

To 21a (183mg, 0.88mmol) was added DMF (5mL), K₂CO₃(364mg, 2.6mmol), TEA (0.3mL, 1.8mmol) and Compound 2(300mg, 0.88mmol) were heated to 65 ℃ and stirred for 3 h. After the reaction was completed, the mixture was cooled to room temperature, DMF was spin-dried under reduced pressure, and DCM (10mL) was added to dissolve the DMF, the DMF was washed with water 1 time (5mL), saturated brine was washed with water 1 time (5mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated to dryness, prepared into sand, and separated and purified by column chromatography (DCM: MeOH 60: 1-20: 1) to obtain a red solid 22a (226mg, 50%).¹H NMR(300MHz,DMSO-d)δ:9.27(s,1H),7.71(d,J＝8.5Hz,2H),7.51(d,J＝8.4Hz,1H),7.37(d,J＝8.4Hz,1H),6.71(d,J＝8.4Hz,2H),4.62(d,J＝5.5Hz,2H),4.36(t,J＝5.5Hz,1H),3.20–3.05(m,2H),2.29(s,3H),1.79–1.71(m,2H),1.68–1.59(m,2H),1.47(s,9H),1.31(s,6H).

Step three: synthesis of 1- (pyridin-4-yl-methyl) -3- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) phenyl) urea (S42)

Weighing 22a (220mg, 0.43mmol), adding 1mL of ethyl acetate, adding 1mL of HCl/ethyl acetate solution (3M) into the suspension, stirring at room temperature for 3h, directly filtering after the reaction is completed, washing a filter cake with ethyl acetate, and drying in vacuum to obtain a hydrochloride, wherein the hydrochloride is directly reacted in the next step without purification. To the hydrochloride was added 5mL of anhydrous THF and TEA (0.36mL, 2.58mmol) was added. The prepared isocyanate 20a was dissolved in anhydrous THF (2mL), added dropwise to the above solution slowly at 0 deg.C, and transferred to room temperature for overnight reaction. The solvent is removed under reduced pressure, DCM (10mL) is added for dissolving, washing is carried out once (10mL), saturated saline solution is carried out once (10mL), anhydrous sodium sulfate is dried, filtering is carried out, the solvent is evaporated to dryness, sand is prepared, and column chromatography separation and purification (DCM: MeOH: 60: 1-20: 1) are carried out to obtain a red solid 42.

¹H NMR(300MHz,DMSO-d)δ8.49(d,J＝6.1Hz,1H),8.19(s,2H),7.68–7.60(m,1H),7.51(m,2H),7.51(d,J＝8.4Hz,1H),7.38(d,J＝8.4Hz,1H),7.26–7.19(m,2H),6.58(t,J＝6.1Hz,2H),6.54–6.50(m,2H),4.67(dd,J＝13.4,5.8Hz,4H),4.36(t,J＝5.5Hz,1H),3.17–3.05(m,2H),2.26(s,3H),1.84–1.71(m,2H),1.64–1.59(m,2H),1.31(s,6H).¹³C NMR(75MHz,DMSO-d6)δ:180.5,176.8,158.6,156.6,149.5,148.0,145.7,142.4,141.0,139.5,136.0,128.6,128.2,127.7,122.5,121.5,121.4,118.3,117.8,115.6,44.0,40.4,38.9,34.8,31.1,29.5,19.2,9.9.

Example 43: synthesis of 1- (pyridin-3-yl-methyl) -3- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) aminobutyl) urea (S43)

The synthesis was as in example 42, except that the corresponding starting materials were replaced.¹H NMR(500MHz,Chloroform-d)δ:8.61(s,1H),7.72(dt,J＝7.9,2.1Hz,1H),7.50(d,J＝8.4Hz,1H),7.35(d,J＝8.4Hz,2H),7.27(dd,J＝7.9,3.5Hz,1H),6.32(t,J＝6.1Hz,1H),5.94(t,J＝4.3Hz,1H),4.53(m,4H),4.01(d,J＝6.0Hz,2H),3.23–3.04(m,2H),2.73(m,2H),2.36(s,3H),1.81–1.71(m,2H),1.66–1.59(m,4H),1.57–1.48(m,2H),1.31(s,6H).¹³C NMR(125MHz,DMSO-d6)δ:180.5,176.7,158.8,158.6,153.6,148.5,148.3,148.0,142.3,135.1,133.7,128.6,128.2,127.7,123.8,121.4,118.3,114.4,48.3,46.1,42.0,39.0,38.2,34.8,31.10,29.5,26.3,26.0,19.2,9.9.

Example 44: synthesis of 2- (pyridin-3-yl) -N- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) amino) phenyl) cyclopropyl-1-carboxamide (S44)

The method comprises the following steps: synthesis of n-butyl (E) -3- (pyridin-3-yl) acrylate (25a)

To 3-bromopyridine (1.57g, 9.94mmol) was added DMF (10mL) followed by butyl acrylate (1.92g, 15mmol) Pd (OAc)₂(23mg，0.001mmol)，PPh₃(52mg，0.002mmol)，K₂CO₃(2.76g, 20mmol), heating to 139 ℃ under the protection of nitrogen, and stirring for reaction for 20 h. Cooling to room temperature, filtering, concentrating the filtrate, dissolving with EA (20mL), washing with water (5 mL. times.3), washing with saturated saline once (10mL), drying over anhydrous sodium sulfate, filtering, and steamingThe solvent was dried to give 25a (1.6g) as a red oil.

Step two: (E) synthesis of (26a) -3- (pyridin-3-yl) acrylic acid

KOH (918mg, 16.4mmol) was dissolved in 10mL of water, and the aqueous KOH solution was added to a solution of 25a (1.6g, 7.8mmol) in ethanol (20mL) and stirred at room temperature for 20 h. After the reaction was complete, the pH was adjusted to 6.0 with 12M HCl solution, filtered and the filter cake was dried under vacuum to give compound 26a (1.14g, 98%).

Step three: (E) synthesis of (E) -N-methoxy-N-methyl-3- (pyridin-3-yl) acrylamide (27a)

26a (1.0g, 6.71mmol) and N, O-dimethylhydroxylamine hydrochloride (1.3g, 13.22mmol) were dissolved in DCM (10mL), EDCI (1.3g, 6.71mmol) and DMAP (820mg, 6.71mmol) were added to the above solution in this order, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, 5mL of lcm was added to dilute the reaction mixture, washed once with water (5mL), washed once with saturated saline (10mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to obtain a yellow oily substance 27a, which was directly put into the next reaction.

Step four: synthesis of N-methoxy-N-methyl 2- (pyridin-3-yl) cyclopropyl-1-carboxamide (29a)

NaH (640mg, 16mmol) was added to a solution of trimethyl sulfoxide iodide (2.2g, 10mmol) in DMSO (10mL) at 0 deg.C, then transferred to room temperature and stirred for 1 h. Feed 27a (960mg, 5mmol) was added to the above solution and stirred for 1 h. After the reaction is completed, saturated NH is added into the reaction₄Cl (8mL), ethyl acetate extraction (10mL × 3), combined organic phases, washed with water (10mL × 3), dried over anhydrous sodium sulfate, filtered, solvent evaporated to dryness, sand made, and purified by column chromatography (DCM: MeOH ═ 5:1) to give yellow oil 29a (824mg, 80%).

Step four: synthesis of 2- (pyridin-3-yl) cyclopropyl-1-carboxylic acid (30a)

KOH (647mg, 11.6mmol) was dissolved in 10mL of water, and the aqueous KOH solution was added to a solution of 29a (800g, 3.88mmol) in ethanol (15mL) and stirred at room temperature for 24 h. After the reaction was complete, 10mL of water was added, DCM (3X 5mL) was extracted, the pH of the aqueous phase was adjusted to 6.0 with 12M HCl solution, then water was spun off under reduced pressure, the solid obtained by vacuum drying was slurried with methanol (20mL), the insoluble solid was removed by filtration to give a suction filtration, and the filtrate was concentrated to give a pale yellow solid. Recrystallization from ethyl acetate/methanol (5:1) gave pure 30a (341mg, 54%).

Step five: synthesis of 2- (pyridin-3-yl) cyclopropyl-1-carbonyl chloride (31a)

To a solution of 30a (341mg, 2.1mmol) in DCM was added thionyl chloride (0.35mL, 4.8mmol) and the temperature was raised to 40 ℃. And reacting for 5 hours. After the reaction is completed, the solvent is removed by spinning off to obtain an off-white crude product 31a, which is directly put into the next reaction.

Step six: synthesis of 1- (pyridin-3-yl-methyl) -3- (4- (((1,6, 6-trimethyl-10, 11-dione-6, 7,8,9,10, 11-hexahydro-phenanthro [1,2-b ] furan-2-yl) methyl) aminobutyl) urea (S43)

Weighing 22a (220mg, 0.43mmol), adding 1mL of ethyl acetate, adding 1mL of HCl/ethyl acetate solution (3M) into the suspension, stirring at room temperature for 3h, directly filtering after the reaction is completed, washing a filter cake with ethyl acetate, and drying in vacuum to obtain a hydrochloride, wherein the hydrochloride is directly reacted in the next step without purification. To the hydrochloride was added 5mL of anhydrous DCM and TEA (0.36mL, 2.58 mmol). The above solution was added dropwise to the prepared acid chloride 31a in anhydrous DCM at 0 ℃ and the reaction was stirred at rt for 3 h. After completion of the reaction, DCM (10mL) was added to dilute the reaction mixture, washed once with water (10mL), washed once with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered and the solvent was evaporated to dryness to give S44(161mg, 67%) as a red solid.

¹H NMR(300MHz,Chloroform-d)δ:9.48(s,1H),8.56(dt,J＝4.8,1.8Hz,1H),8.44(t,J＝1.8Hz,1H),7.68–7.58(m,2H),7.55(dt,J＝7.7,1.8Hz,1H),7.51(d,J＝8.4Hz,1H),7.39(d,J＝8.4Hz,1H),7.29(dd,J＝7.8,4.8Hz,1H),6.72–6.61(m,2H),4.72(dd,J＝15.0,5.5Hz,1H),4.58(dd,J＝15.1,5.6Hz,1H),4.48(t,J＝5.5Hz,1H),3.16–3.05(m,2H),2.57(dt,J＝7.9,6.4Hz,1H),2.33(dt,J＝7.9,7.1Hz,1H),2.27(s,3H),1.79–1.71(m,2H),1.66–1.59(m,3H),1.38–1.31(m,4H),1.28(s,3H).¹³C NMR(125MHz,Chloroform-d)δ:180.5,176.7,172.1,158.6,149.3,148.1,148.0,142.4,141.1,139.5,134.7,134.4,132.5,128.6,128.2,127.7,123.8,122.6,121.4,117.8,117.8,115.7,40.4,38.9,34.8,31.1,29.5,28.2,23.9,19.2,17.1,9.9.

Example 45: synthesis of 2- (pyridin-3-yl) -N- (4- (((1,6, 6-trimethyl 10, 11-dione-6, 7,8,9,10, 11-hexahydrophenanthrene [1,2-b ] furan-2-yl) methyl) amino) butyl) cyclopropyl-1-carboxamide (S45)

The synthesis was as in example 44, with only the corresponding starting materials being replaced.¹H NMR(500MHz,Chloroform-d)δ8.56(dt,J＝4.8,1.8Hz,1H),8.45(t,J＝1.9Hz,1H),7.56(dt,J＝7.9,1.9Hz,1H),7.50(d,J＝8.4Hz,1H),7.37(d,J＝8.4Hz,1H),7.29(dd,J＝7.9,4.7Hz,1H),7.08(t,J＝4.4Hz,1H),4.06(dd,J＝14.9,5.9Hz,1H),3.95(dd,J＝14.9,5.9Hz,1H),3.31(dtd,J＝14.3,6.2,4.3Hz,1H),3.13–3.07(m,2H),3.03(dtd,J＝14.3,6.3,4.4Hz,1H),2.84(dtd,J＝14.5,6.3,4.1Hz,1H),2.66(dtd,J＝14.5,6.3,4.1Hz,1H),2.59–2.47(m,2H),2.25(s,3H),2.28–2.19(m,1H),1.75(tdd,J＝6.2,5.6,4.7Hz,2H),1.66–1.45(m,6H),1.49–1.37(m,1H),1.38–1.26(m,6H).¹³C NMR(125MHz,Common NMR Solvents)δ180.5,176.1,173.6,158.6,153.6,149.3,148.1,148.0,142.3,134.7,132.5,128.6,128.2,127.7,123.8,121.4,118.3,114.4,48.3,46.1,39.1,39.0,34.8,31.1,29.5,27.3,26.5,26.0,23.9,19.2,17.2,9.9.

Example 46: determination of the metabolic Rate of Compounds reduced by NQO1

The experimental method comprises the following steps: NADPH can be oxidized to NADP in the presence of NQO1 and quinones, which leads to a decrease in absorbance at 340 nM. The reaction was initiated by first incubating the compound with NQO1 for 10min at 37 ℃ and adding NADPH, and the change in absorbance at 340nM was monitored over 5min (every 2 s). The reduction rate was expressed as μmol NADPH/min/. mu.mol NQO 1. The metabolic rates for NQO1 for some of the compounds of the invention are shown in table 1.

Example 47: NAMPT Activity assay

The experimental method comprises the following steps: buffer 1 was prepared from 10. mu.L of 10 XNAMPT buffer, 10. mu.L of 10 XNicotinamide, 10. mu.L of 10 XPRPP, 10. mu.L of 10 XATP 10. mu.L, 2. mu.L of NMNAT1 enzyme, and 48. mu.L of heavy water to 90. mu.L. Buffer 2 was prepared containing 50 XWST-12. mu.L, 50 XADH 2. mu.L, 50 XDiaphorase 2. mu.L, 10 XEtOH 10. mu.L and 4. mu.L of weighted water to a volume of 20. mu.L. mu.L of buffer 1 was added to each well of the plate, followed by 2. mu.L of 50 Xcompound, 2. mu.L DMSO was added to the blank control, and 2. mu.L FK866(1mM) was added to the positive control. mu.L of recombinant NAMPT was added to each well to initiate the enzymatic reaction, mixed well and incubated at 30 ℃ for 60 min. After the reaction is finished, 20 mu L of buffer solution 2 is added for color development, and the absorption value at 450nm of the reaction time of 5-35min is dynamically detected. The results of the NAMPT enzyme inhibitory activity assay of the partial compounds of the invention are shown in table 2.

Example 48: antiproliferative activity of Compounds on tumor cells

The experimental principle is as follows: inhibition of cancer cell growth by compounds was measured by the MTT method. The principle of the MTT method is that yellow thiazole blue can penetrate through a cell membrane to enter a cell, amber dehydrogenase in mitochondria of a living cell can reduce exogenous MTT into blue-purple needle-shaped Formazan crystals which are difficult to dissolve in water and deposit the crystals in the cell, the crystals can be dissolved by dimethyl sulfoxide (DMSO), an enzyme linked immunosorbent detector is used for detecting the light absorption value at the wavelength of 490nm/570nm, and the cell quantity can be indirectly reflected.

Experimental materials: the cancer cell lines used are NQO1 and human breast cancer cell MCF-7 cell with high NAMPT expression, human non-small cell lung cancer cell A549, human pancreatic cancer cell MiaPaca2 and human prostate cancer cell PC3 which are respectively cultured by DMEM + 10% FBS culture medium or 1640+ 10% FBS culture medium.

Experimental methods and analysis of results:

experimental groups: 190. mu.l cell suspension + 10. mu.l drug at different concentrations

Blank control group: 200 μ l PBS

Negative control group: 190. mu.l of cell suspension + 10. mu.l of 2% DMSO (final DMSO concentration: 0.1%)

Positive control group: 190. mu.l cell suspension + 10. mu.l of different concentrations of the compound

a) Cells were seeded in 96-well plates at 1500/well, 190. mu.l/well, 5% CO at 37 ℃₂Culturing in an incubator overnight;

b) adding 10 μ l of different drugs into each well the next day, and arranging three parallel wells; 37 ℃ and 5% CO₂Incubating the incubator for 8 hours, sucking out the culture medium, and replacing the culture medium with a new one;

c) mu.l of 5mg/ml MTT, 5% CO at 37 ℃ were added to each well₂Incubating in an incubator for 4 hours;

d) discarding the supernatant, adding 100 μ l DMSO into each well, and oscillating;

e) reading at 570nm, calculating cell survival rate, and calculating IC according to the result₅₀The results are shown in Table 3.

The o-quinone compounds provided in the embodiments of the present invention, and the pharmaceutical compositions and applications thereof are described in detail above, and the principles and embodiments of the present invention are explained in the present specification by using specific examples, and the description of the above examples is only used to help understanding the method and the core concept of the present invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.

Claims

1. An o-quinone compound shown in formula I, or pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof:

in formula I:

r is unsubstituted or R¹Substituted C_6-10Aryl, unsubstituted or R²Substituted 'hetero atom selected from one or more of N, O and S, 5-10 membered heteroaryl with 1-3 hetero atoms', unsubstituted or R³A substituted 5-to 10-membered heterocycloalkyl group containing one or more heteroatoms selected from N, O and S and having 1 to 3 heteroatoms; wherein R is¹、R²And R³Independently is deuterium, halogen, hydroxy, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6A haloalkyl group;

y is a single bond, C_2-4Olefinic bond, C_1-4Alkyl, cyclopropyl, -NHCH₂-；

E is O, S or N-C ≡ N;

l is-NR⁴-(CH₂)n-、

Wherein R is⁴And R⁵Independently selected from hydrogen, C₁-₆Alkyl, hydroxy- (C)_1-6Alkyl) -, C_6-10Aryl radical, C₃-C₆Cycloalkyl radical, C_6-10Aryl radical- (C)_1-6Alkyl) -, C₃-C₆Cycloalkyl- (C)_1-6Alkyl) -, or

n＝0-8。

2. The o-quinone compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof, wherein R is unsubstituted or R²When the substituted 'hetero atom is selected from one or more of N, O and S, and 5-to 10-membered heteroaryl having 1 to 3 hetero atoms', R is²Is one or more, when there are more than one R²Said R is²May be the same or different;

and/or, when R is unsubstituted or R²When the substituted 'heteroatom is selected from one or more of N, O and S and 5-10 membered heteroaryl with 1-3 heteroatoms', the heteroaryl is '5-10 membered heteroaryl with one or more heteroatoms selected from N, O and S, 1-3 heteroatoms and at least 1N atom';

and/or, when R is unsubstituted or R³When the substituted 'hetero atom is selected from one or more of N, O and S, and the hetero atom number is 5-10-membered with 1-3', the R is³Is one or more, when there are more than one R³When R is said³The same or different;

and/or, when R is unsubstituted or R³When the substituted 'heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3, namely the heterocycloalkyl is 5-10-membered', the heterocycloalkyl is 'the heterocycloalkyl, the heteroatom is selected from one or more of N, O and S, the number of heteroatoms is 1-3, and the number of N atoms is at least 1, and is 5-10-membered';

when R is²Is C_1-6When there is an alkyl group, said C_1-6Alkyl of (A) is C_1-3An alkyl group; when R is²Is C_1-6Alkoxy of (2), said C_1-6Alkoxy of C_1-3An alkoxy group; when R is²Is C_1-6When halogenated alkyl, said C_1-6Haloalkyl being C_1-3A haloalkyl group; when R is²Is C_1-6When there is an alkyl group, said C_1-6Alkyl of (A) is C_1-3An alkyl group; when R is²Is C_1-6Alkoxy of (2), said C_1-6Alkoxy of C_1-3An alkoxy group; when R is²Is C_1-6When halogenated alkyl, said C_1-6Haloalkyl being C_1-3A haloalkyl group.

When E is O, Y is a single bond, C_1-4Alkyl radical, C_2-4Alkenyl, cyclopropyl, -NH-CH₂-, or, when E is S, Y is-NH-CH₂-or, alternatively, when E is N-C ≡ N, Y is a single bond;

when L is-NR⁴-(CH₂) When n-is, n is 2-6; when L is selected from

When n is 0-2;

when R is⁴Is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group; when R is⁴Is hydroxy- (C)_1-6Alkyl) -hydroxy- (C)_1-6Alkyl) -is hydroxy- (C)_1-4Alkyl) -; when R is⁴Is C_6-10When aryl, said C_6-10Aryl is phenyl; when R is⁴Is C_6-10Aryl radical- (C)_1-6Alkyl) -said C_6-10Aryl radical- (C)_1-6Alkyl) -is phenyl- (C)_1-4Alkyl) -; when R is⁴Is C₃-C₆Cycloalkyl- (C)_1-6Alkyl) -said C₃-C₆Cycloalkyl- (C)_1-6Alkyl) -is C₃-C₆Cycloalkyl- (C)_1-4Alkyl groups).

3. The o-quinone compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof, wherein R is unsubstituted or R²When the substituted 'hetero atom is selected from one or more of N, O and S, and 5-10 membered heteroaryl with 1-3 hetero atoms', R is³The number of (a) is 1,2 or 3;

and/or, when R is unsubstituted or R²When the substituted ' 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S ' is substituted ', the heteroaryl is:

and/or, when R is unsubstituted or R³When the substituted 5-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms and one or more hetero atoms selected from N, O and S is substituted, the heterocycloalkyl is

And/or when R⁴Is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, isopropyl;

and/or when R⁴Is C_6-10Aryl radical- (C)_1-6Alkyl) -said C_6-10Aryl radical- (C)_1-6Alkyl) -is benzyl, phenethyl, phenylpropyl, preferably benzyl.

4. The o-quinone compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof, wherein R is unsubstituted or R²When substituted with a 5-to 10-membered heteroaryl group having 1 to 3 hetero atoms and one or more hetero atoms selected from N, O and S, the group is unsubstituted or R²Substituted heteroaryl groups are:

and/or, when R is unsubstituted or R³Substituted 5-to 10-membered hetero atom containing 1 to 3 hetero atoms selected from N, O and SWhen cycloalkyl is said unsubstituted or R³Substituted heterocycloalkyl is:

5. the O-quinone compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof, wherein when E is O, Y is a single bond, R is:

or, when E is O, Y is-NH-CH₂-、C_2-4Alkenyl or cyclopropyl, R is:

or, when E is S, Y is-NH-CH₂-, R is:

or, when E is N-C ≡ N, Y is C_1-4Alkyl, R is:

or, when E is O, Y is cyclopropyl and R is:

6. the o-quinone compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof, wherein the o-quinone compound is any one of the following compounds:

7. a method of synthesis of a compound according to any one of claims 1 to 6, the route being as follows:

the method comprises the following steps:

(1) performing chloromethylation reaction on the compound 1 under the action of HCl gas to obtain a compound 2, wherein the reaction time is 1.5-3 h, the reaction temperature is 45-65 ℃, and the reaction solvent is selected from 1, 4-dioxane, ethyl acetate and tetrahydrofuran;

(2) and carrying out substitution reaction on the compound 2 and the intermediate compound II to generate a compound I, wherein the reaction temperature is 45-65 ℃, and the reaction solvent is selected from acetone, acetonitrile, tetrahydrofuran and N, N-dimethylformamide.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof, and a pharmaceutically acceptable excipient.

9. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, prodrug, racemate or isomer thereof, or a pharmaceutical composition according to claim 8, for use in the preparation of reduced coenzyme I: quinone oxidoreductase substrates and nicotinamide phosphoribosyltransferase inhibitors.

10. Use of the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, prodrug, racemate or isomer thereof, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for preventing and/or treating tumors, wherein the tumors are one or more of breast cancer, ovarian cancer, prostate cancer, colon cancer, gastric cancer, non-small cell lung cancer, head and neck cell cancer, glioma, bladder cancer, kidney cancer, cholangiocarcinoma, esophageal squamous carcinoma, pancreatic cancer, liver cancer, brain cancer, melanoma, skin cancer, leukemia and cervical cancer.